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Baysoy A, Tian X, Zhang F, Renauer P, Bai Z, Shi H, Li H, Tao B, Yang M, Enninful A, Gao F, Wang G, Zhang W, Tran T, Patterson NH, Bao S, Dong C, Xin S, Zhong M, Rankin S, Guy C, Wang Y, Connelly JP, Pruett-Miller SM, Chi H, Chen S, Fan R. Spatially Resolved in vivo CRISPR Screen Sequencing via Perturb-DBiT. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.624106. [PMID: 39605490 PMCID: PMC11601513 DOI: 10.1101/2024.11.18.624106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Perturb-seq enabled the profiling of transcriptional effects of genetic perturbations in single cells but lacks the ability to examine the impact on tissue environments. We present Perturb-DBiT for simultaneous co-sequencing of spatial transcriptome and guide RNAs (gRNAs) on the same tissue section for in vivo CRISPR screen with genome-scale gRNA libraries, offering a comprehensive understanding of how genetic modifications affect cellular behavior and tissue architecture. This platform supports a variety of delivery vectors, gRNA library sizes, and tissue preparations, along with two distinct gRNA capture methods, making it adaptable to a wide range of experimental setups. In applying Perturb-DBiT, we conducted un-biased knockouts of tens of genes or at genome-wide scale across three cancer models. We mapped all gRNAs in individual colonies and corresponding transcriptomes in a human cancer metastatic colonization model, revealing clonal dynamics and cooperation. We also examined the effect of genetic perturbation on the tumor immune microenvironment in an immune-competent syngeneic model, uncovering differential and synergistic perturbations in promoting immune infiltration or suppression in tumors. Perturb-DBiT allows for simultaneously evaluating the impact of each knockout on tumor initiation, development, metastasis, histopathology, and immune landscape. Ultimately, it not only broadens the scope of genetic inquiry, but also lays the groundwork for developing targeted therapeutic strategies.
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Affiliation(s)
- Alev Baysoy
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- These authors contributed equally
| | - Xiaolong Tian
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- These authors contributed equally
| | - Feifei Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- These authors contributed equally
| | - Paul Renauer
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- These authors contributed equally
| | - Zhiliang Bai
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Hao Shi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Haikuo Li
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Bo Tao
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Mingyu Yang
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Archibald Enninful
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Fu Gao
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Guangchuan Wang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | | | | | | | - Shuozhen Bao
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Chuanpeng Dong
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - Shan Xin
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - Mei Zhong
- Department of Cell Biology, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Sherri Rankin
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Cliff Guy
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Yan Wang
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jon P. Connelly
- Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | | | - Hongbo Chi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Systems Biology Institute, Integrated Science & Technology Center, West Haven, CT, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
- Yale Stem Cell Center and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
- Human and Translational Immunology, Yale University School of Medicine, New Haven, CT 06520, USA
- Lead contact
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Ciepiela I, Szczepaniak M, Ciepiela P, Hińcza-Nowak K, Kopczyński J, Macek P, Kubicka K, Chrapek M, Tyka M, Góźdź S, Kowalik A. Tumor location matters, next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients. Sci Rep 2024; 14:4619. [PMID: 38409377 PMCID: PMC10897470 DOI: 10.1038/s41598-024-55139-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 02/20/2024] [Indexed: 02/28/2024] Open
Abstract
Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy.
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Affiliation(s)
- Izabela Ciepiela
- Radiotherapy Department, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Magdalena Szczepaniak
- Department of Molecular Diagnostics, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Przemysław Ciepiela
- Surgical Oncology Department, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Kinga Hińcza-Nowak
- Department of Molecular Diagnostics, Holy Cross Cancer Centre, 25-734, Kielce, Poland
- Endocrinology Clinic, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Janusz Kopczyński
- Surgical Pathology, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Paweł Macek
- Collegium Medicum, Jan Kochanowski University, 25-319, Kielce, Poland
- Department of Epidemiology and Cancer Control, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Kamila Kubicka
- Department of Molecular Diagnostics, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Magdalena Chrapek
- Department of Mathematics, Faculty of Natural Sciences, Jan Kochanowski University, 25-406, Kielce, Poland
| | - Magdalena Tyka
- Department of Molecular Diagnostics, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Stanisław Góźdź
- Collegium Medicum, Jan Kochanowski University, 25-319, Kielce, Poland
- Clinical Oncology Clinic, Holy Cross Cancer Centre, 25-734, Kielce, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holy Cross Cancer Centre, 25-734, Kielce, Poland.
- Division of Medical Biology, Institute of Biology, Jan Kochanowski University, 25-406, Kielce, Poland.
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Gofrit ON, Gofrit B, Roditi Y, Popovtzer A, Frank S, Sosna J, Orevi M, Goldberg SN. The different clonal origins of metachronous and synchronous metastases. J Cancer Res Clin Oncol 2023; 149:11085-11092. [PMID: 37340186 PMCID: PMC10465669 DOI: 10.1007/s00432-023-05007-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 06/16/2023] [Indexed: 06/22/2023]
Abstract
BACKGROUND Metastases are the leading cause of mortality in cancer patients. Linear and parallel are the two prominent models of metastatic progression. Metastases can be detected synchronously along with the primary tumor or metachronously, following treatment of localized disease. The aim of the study was to determine whether synchronous metastases (SM) and metachronous metastases (MM) differ only in lead-time or stem from different biological processes. MATERIALS AND METHODS We retrospectively studied the chest CTs of 791 patients inflicted by eleven malignancy types that were treated in our institution in the years 2010-2020. Patient's population included 396 with SM and 395 with MM. The diameter of 15,427 lung metastases was measured. Clonal origin was deduced from the linear/parallel ratio (LPR)-a computerized analysis of metastases diameters. LPR of 1 suggests pure linear dissemination and - 1 pure parallel. RESULTS Patients with MM were significantly older (average of 62.9 vs 60.7 years, p = 0.02), and higher percentage of them were males (58.7% vs 51.1%, p = 0.03). Median overall survival of patients with MM and SM was remarkably similar (23 months and 26 months respectively, p = 0.774) when calculated from the time of metastases diagnosis. Parallel dissemination (LPR ≤ 0) was found in 35.4% of patients with MM compared to only 19.8% of the patients with SM (p < 0.00001). CONCLUSION Patients with SM and MM differ in demography and in clonal origin. Different therapeutic approaches may be considered in these two conditions.
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Affiliation(s)
- Ofer N Gofrit
- Department of Urology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, P.O.B 12000, 91120, Jerusalem, Israel.
| | - Ben Gofrit
- School of Engineering and Computer Science, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yuval Roditi
- School of Engineering and Computer Science, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Aron Popovtzer
- Department of Oncology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Steve Frank
- Department of Oncology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Jacob Sosna
- Department of Radiology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Marina Orevi
- Department of Nuclear Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - S Nahum Goldberg
- Department of Radiology, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
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Schmid S, Becker H, Fritsch R, Bausch J, Hunter N, Jenkner C, Hassan M, Passlick B. Study Protocol for a Randomised Controlled Trial on Pulmonary Metastasectomy vs. Standard of Care in Colorectal Cancer Patients With ≥ 3 Lung Metastases (PUCC-Trial). Front Oncol 2022; 12:913896. [PMID: 35898865 PMCID: PMC9313587 DOI: 10.3389/fonc.2022.913896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/19/2022] [Indexed: 11/15/2022] Open
Abstract
This is a multicentre prospective randomised controlled trial for patients with 3 or more resectable pulmonary metastases from colorectal carcinoma. The study investigates the effects of pulmonary metastasectomy in addition to standard medical treatment in comparison to standard medical treatment plus possible local ablative measures such as SBRT. This trial is intended to demonstrate an overall survival difference in the group undergoing pulmonary metastasectomy. Further secondary and exploratory endpoints include quality of life (EORTC QLQ-C30, QLQ-CR29 and QLQ-LC29 questionnaires), progression-free survival and impact of mutational status. Due to the heterogeneity and complexity of the disease and treatment trajectories in metastasised colorectal cancer, well powered trials have been very challenging to design and execute. The goal of this study is to create a setting which allows treatment as close to the real life conditions as possible but under well standardised conditions. Based on previous trials, in which patient recruitment in the given setting hindered successful study completion, we decided to (1) restrict inclusion to patients with 3 or more metastases (since in case of lesser, surgery will probably be the preferred option) and (2) allow for real world standard of care (SOC) treatment options before and after randomisation including watchful waiting (as opposed to a predefined treatment protocol) and (3) possibility that patient can receive SOC externally (to reduce patient burden). Moreover, we chose to stipulate 12 weeks of systemic treatment prior to possible resection to further standardize treatment response and disease course over a certain period of time. Hence, included patients will be in the disease state of oligopersistence rather than primary oligometastatic. The trial was registered in the German Clinical Trials Register (DRKS-No.: DRKS00024727).
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Affiliation(s)
- Severin Schmid
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Heiko Becker
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ralph Fritsch
- Department of Medical Oncology and Hematology - University Hospital of Zurich, Zurich, Switzerland
| | - Johannes Bausch
- Clinical Trials Unit, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Natalie Hunter
- Clinical Trials Unit, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Carolin Jenkner
- Clinical Trials Unit, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mohamed Hassan
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bernward Passlick
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Yamada T, Nakanishi Y, Hayashi H, Tanishima S, Mori R, Fujii K, Okamura K, Tsuchikawa T, Nakamura T, Noji T, Asano T, Matsui A, Tanaka K, Watanabe Y, Kurashima Y, Ebihara Y, Murakami S, Shichinohe T, Mitsuhashi T, Hirano S. Targeted amplicon sequencing for primary tumors and matched lymph node metastases in patients with extrahepatic cholangiocarcinoma. HPB (Oxford) 2022; 24:1035-1043. [PMID: 34903468 DOI: 10.1016/j.hpb.2021.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lymph node metastasis (LNM) is one of the most adverse prognostic factors in extrahepatic cholangiocarcinoma (EHCC) cases. As next-generation sequencing technology has become more widely available, the genomic profile of biliary tract carcinoma has been clarified. However, whether LNMs have additional genomic alterations in patients with EHCC has not been investigated. Here, we aimed to compare the genomic alterations between primary tumors and matched LNMs in patients with EHCC. METHODS Sixteen patients with node-positive EHCCs were included. Genomic DNA was extracted from tissue samples of primary tumors and matched LNMs. Targeted amplicon sequencing of 160 cancer-related genes was performed. RESULTS Among the 32 tumor samples from 16 patients, 91 genomic mutations were identified. Genomic mutations were noted in 31 genes, including TP53, MAP3K1, SMAD4, APC, and ARID1A. TP53 mutations were most frequently observed (12/32; 37.5%). Genomic mutation profiles were highly concordant between primary tumors and matched LNMs (13/16; 81.3%), and an additional genomic mutation of CDK12 was observed in only one patient. CONCLUSION Genomic mutations were highly concordant between primary tumors and matched LNMs, suggesting that genotyping of archived primary tumor samples may help predict genomic mutations of metastatic tumors in patients with EHCC.
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Affiliation(s)
- Toru Yamada
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan; Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan.
| | - Hideyuki Hayashi
- Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan; Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | | | - Ryo Mori
- Mitsubishi Space Software, Tokyo, Japan
| | - Kyoko Fujii
- Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan; Department of Cancer Pathology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Aya Matsui
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yusuke Watanabe
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yo Kurashima
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yuma Ebihara
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Soichi Murakami
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
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Cowan RW, Pratt ED, Kang JM, Zhao J, Wilhelm JJ, Abdulla M, Qiao EM, Brennan LP, Ulintz PJ, Bellin MD, Rhim AD. Pancreatic Cancer-Related Mutational Burden Is Not Increased in a Patient Cohort With Clinically Severe Chronic Pancreatitis. Clin Transl Gastroenterol 2021; 12:e00431. [PMID: 34797250 PMCID: PMC8604013 DOI: 10.14309/ctg.0000000000000431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/30/2021] [Indexed: 11/30/2022] Open
Abstract
INTRODUCTION Chronic pancreatitis is associated with an increased risk of developing pancreatic cancer, and patients with inherited forms of pancreatitis are at greatest risk. We investigated whether clinical severity of pancreatitis could also be an indicator of cancer risk independent of etiology by performing targeted DNA sequencing to assess the mutational burden in 55 cancer-associated genes. METHODS Using picodroplet digital polymerase chain reaction and next-generation sequencing, we reported the genomic profiles of pancreases from severe clinical cases of chronic pancreatitis that necessitated palliative total pancreatectomy with islet autotransplantation. RESULTS We assessed 57 tissue samples from 39 patients with genetic and idiopathic etiologies and found that despite the clinical severity of disease, there was no corresponding increase in mutational burden. The average allele frequency of somatic variants was 1.19% (range 1.00%-5.97%), and distinct regions from the same patient displayed genomic heterogeneity, suggesting that these variants are subclonal. Few oncogenic KRAS mutations were discovered (7% of all samples), although we detected evidence of frequent cancer-related variants in other genes such as TP53, CDKN2A, and SMAD4. Of note, tissue samples with oncogenic KRAS mutations and samples from patients with PRSS1 mutations harbored an increased total number of somatic variants, suggesting that these patients may have increased genomic instability and could be at an increased risk of developing pancreatic cancer. DISCUSSION Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer-related mutational burden is not appreciably increased.
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Affiliation(s)
- Robert W. Cowan
- Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
- Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
| | - Erica D. Pratt
- Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
- Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
| | - Jin Muk Kang
- Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
- Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
| | - Jun Zhao
- Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
- Department of Translational Molecular Pathology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Joshua J. Wilhelm
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA;
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, Minnesota, USA;
| | - Muhamad Abdulla
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, Minnesota, USA;
| | - Edmund M. Qiao
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA;
| | - Luke P. Brennan
- University of Michigan Medical School, Ann Arbor, Michigan, USA;
| | - Peter J. Ulintz
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA;
- BRCF Bioinformatics Core, University of Michigan, Ann Arbor, Michigan, USA.
| | - Melena D. Bellin
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA;
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, Minnesota, USA;
| | - Andrew D. Rhim
- Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
- Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA;
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Ottaiano A, Petito A, Santorsola M, Gigantino V, Capuozzo M, Fontanella D, Di Franco R, Borzillo V, Buonopane S, Ravo V, Scipilliti E, Totaro G, Serra M, Ametrano G, Penta R, Tatangelo F, Scognamiglio G, Di Mauro A, Di Bonito M, Napolitano M, Scala S, Rea G, Santagata S, Lombardi A, Grimaldi A, Caputo C, Crispo A, Celentano E, De Feo G, Circelli L, Savarese G, Ruggiero R, Perri F, Granata V, Botti G, Caraglia M, Nasti G, Muto P. Prospective Evaluation of Radiotherapy-Induced Immunologic and Genetic Effects in Colorectal Cancer Oligo-Metastatic Patients with Lung-Limited Disease: The PRELUDE-1 Study. Cancers (Basel) 2021; 13:4236. [PMID: 34439390 PMCID: PMC8394588 DOI: 10.3390/cancers13164236] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/16/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND in recent years, the management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). The administration of SRT has been demonstrated, particularly in oligo-metastatic (om) CRC, to be a safe and effective option. Interestingly, it has been demonstrated that SRT can induce regression of tumors in non-irradiated regions ("abscopal effect") through stimulation of anti-tumor immune effects ("radiation-induced immunity"). We have recently shown that lung-limited omCRC is characterized by regression of tumor clones bearing specific key driver gene mutations. AIMS to assess the genetic evolution on tumor cancer cells induced by SRT in lung-limited omCRC. Secondary objectives included descriptions of the abscopal effect, responses' duration, toxicity, and progression-free survival. A translational research will be performed to evaluate tumor genetic evolution (through liquid biopsies and Next Generation Sequencing), HLA class I repertoire, peripheral immune cells, and cytokine dynamics. METHODS PRELUDE-1 is a prospective translational study. SRT will be administered only to the largest nodule (with a maximum diameter ≤ 25 mm) in omCRC with two or three radiologically evident lesions. The sample size is based on the innovative hypothesis that radiation-induced immunity could induce regression of tumor clones bearing KRAS oncogene mutations. According to the binomial test, considering the frequency of KRAS mutations and assuming a probability of mutant KRAS→wild type KRAS of p0 = 0.0077, with α = 0.05 and 1-β = 0.60, the final sample size is 25 patients.
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Affiliation(s)
- Alessandro Ottaiano
- SSD—Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.)
| | - Angela Petito
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Mariachiara Santorsola
- SSD—Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.)
| | - Valerio Gigantino
- Innovalab Scarl, Molecular Biology, Centro Direzionale, Isola A2, 80143 Naples, Italy; (V.G.); (M.C.); (D.F.)
| | - Maurizio Capuozzo
- Innovalab Scarl, Molecular Biology, Centro Direzionale, Isola A2, 80143 Naples, Italy; (V.G.); (M.C.); (D.F.)
| | - Daniela Fontanella
- Innovalab Scarl, Molecular Biology, Centro Direzionale, Isola A2, 80143 Naples, Italy; (V.G.); (M.C.); (D.F.)
| | - Rossella Di Franco
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Valentina Borzillo
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Sergio Buonopane
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Vincenzo Ravo
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Esmeralda Scipilliti
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Giuseppe Totaro
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Marcello Serra
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Gianluca Ametrano
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
| | - Roberta Penta
- Oncohaematology Department, A.O.R.N. Santobono-Pausilipon di Napoli, 80123 Naples, Italy;
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (F.T.); (G.S.); (A.D.M.); (M.D.B.)
| | - Giosuè Scognamiglio
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (F.T.); (G.S.); (A.D.M.); (M.D.B.)
| | - Annabella Di Mauro
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (F.T.); (G.S.); (A.D.M.); (M.D.B.)
| | - Maurizio Di Bonito
- Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (F.T.); (G.S.); (A.D.M.); (M.D.B.)
| | - Maria Napolitano
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.N.); (S.S.); (G.R.); (S.S.)
| | - Stefania Scala
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.N.); (S.S.); (G.R.); (S.S.)
| | - Giuseppina Rea
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.N.); (S.S.); (G.R.); (S.S.)
| | - Sara Santagata
- Functional Genomics, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.N.); (S.S.); (G.R.); (S.S.)
| | - Angela Lombardi
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, via de Crecchio 7, 80138 Naples, Italy; (A.L.); (A.G.); (C.C.); (M.C.)
| | - Anna Grimaldi
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, via de Crecchio 7, 80138 Naples, Italy; (A.L.); (A.G.); (C.C.); (M.C.)
| | - Carlo Caputo
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, via de Crecchio 7, 80138 Naples, Italy; (A.L.); (A.G.); (C.C.); (M.C.)
| | - Anna Crispo
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.C.); (E.C.)
| | - Egidio Celentano
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.C.); (E.C.)
| | - Gianfranco De Feo
- Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (G.D.F.); (G.B.)
| | - Luisa Circelli
- AMES, Centro Polidiagnostico Strumentale srl, 80013 Naples, Italy; (L.C.); (G.S.); (R.R.)
| | - Giovanni Savarese
- AMES, Centro Polidiagnostico Strumentale srl, 80013 Naples, Italy; (L.C.); (G.S.); (R.R.)
| | - Raffaella Ruggiero
- AMES, Centro Polidiagnostico Strumentale srl, 80013 Naples, Italy; (L.C.); (G.S.); (R.R.)
| | - Francesco Perri
- Head&Neck Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy;
| | - Vincenza Granata
- Radiology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy;
| | - Gerardo Botti
- Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (G.D.F.); (G.B.)
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, via de Crecchio 7, 80138 Naples, Italy; (A.L.); (A.G.); (C.C.); (M.C.)
| | - Guglielmo Nasti
- SSD—Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.)
| | - Paolo Muto
- Radiotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (A.P.); (R.D.F.); (V.B.); (S.B.); (V.R.); (E.S.); (G.T.); (M.S.); (G.A.); (P.M.)
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8
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Ottaiano A, Santorsola M, Caraglia M, Circelli L, Gigantino V, Botti G, Nasti G. Genetic regressive trajectories in colorectal cancer: A new hallmark of oligo-metastatic disease? Transl Oncol 2021; 14:101131. [PMID: 34034007 PMCID: PMC8144733 DOI: 10.1016/j.tranon.2021.101131] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) originates as consequence of multiple genetic alterations. Some of the involved genes have been extensively studied (APC, TP53, KRAS, SMAD4, PIK3CA, MMR genes) in highly heterogeneous and poly-metastatic cohorts. However, about 10% of metastatic CRC patients presents with an indolent oligo-metastatic disease differently from other patients with poly-metastatic and aggressive clinical course. Which are the genetic dynamics underlying the differences between oligo- and poly-metastatic CRC? The understanding of the genetic trajectories (primary→metastatic) of CRC, in patients selected to represent homogenous clinical models, is crucial to make genotype/phenotype correlations and to identify the molecular events pushing the disease towards an increasing malignant phenotype. This information is crucial to plan innovative therapeutic strategies aimed to reverse or inhibit these phenomena. In the present study, we review the genetic evolution of CRC with the intent to give a developmental perspective on the border line between oligo- and poly-metastatic diseases.
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Affiliation(s)
- Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy.
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via L. De Crecchio, 7 80138, Naples, Italy; Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, 83031, Ariano Irpino, Italy
| | - Luisa Circelli
- AMES-Centro Polidiagnostico Strumentale, 80013, Casalnuovo di Napoli, Italy
| | - Valerio Gigantino
- Innovalab scarl, Molecular Biology, Centro Direzionale, isola A2, 80143, Naples, Italy
| | - Gerardo Botti
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
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9
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Stahler A, Heinemann V, Holch JW, von Einem JC, Westphalen CB, Heinrich K, Schlieker L, Jelas I, Alig AHS, Fischer LE, Weiss L, Modest DP, von Weikersthal LF, Decker T, Kiani A, Moehler M, Kaiser F, Kirchner T, Jung A, Stintzing S. Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3). Int J Cancer 2021; 149:1935-1943. [PMID: 34310714 DOI: 10.1002/ijc.33747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/12/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022]
Abstract
Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.
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Affiliation(s)
- Arndt Stahler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | - Volker Heinemann
- Department of Medicine III, University Hospital, University of Munich, Munich, Germany.,LMU Munich, German Cancer Consortium (DKTK), partner site Munich, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Julian Walter Holch
- Department of Medicine III, University Hospital, University of Munich, Munich, Germany.,LMU Munich, German Cancer Consortium (DKTK), partner site Munich, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Jobst Christian von Einem
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | | | - Kathrin Heinrich
- Department of Medicine III, University Hospital, University of Munich, Munich, Germany
| | | | - Ivan Jelas
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | - Annabel Helga Sophie Alig
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | | | - Lena Weiss
- Department of Medicine III, University Hospital, University of Munich, Munich, Germany
| | - Dominik Paul Modest
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Charité-Universitätsmedizin Berlin, Heidelberg, Germany
| | | | | | - Alexander Kiani
- Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - Markus Moehler
- Department of Internal Medicine I, University Medical Center Mainz, Mainz, Germany
| | | | - Thomas Kirchner
- LMU Munich, German Cancer Consortium (DKTK), partner site Munich, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, University of Munich, Munich, Germany
| | - Andreas Jung
- LMU Munich, German Cancer Consortium (DKTK), partner site Munich, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, University of Munich, Munich, Germany
| | - Sebastian Stintzing
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Charité-Universitätsmedizin Berlin, Heidelberg, Germany
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10
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Wang Z, Zheng X, Wang X, Chen Y, Li Z, Yu J, Yang W, Mao B, Zhang H, Li J, Shen L. Genetic differences between lung metastases and liver metastases from left-sided microsatellite stable colorectal cancer: next generation sequencing and clinical implications. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:967. [PMID: 34277767 PMCID: PMC8267278 DOI: 10.21037/atm-21-2221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Data regarding the clinical characteristics and outcomes of lung metastases (LuM) from colorectal cancer (CRC) are different from those of liver metastases (LiM) from CRC. However, little is known about the genetic features of LuM. This study aimed to identify the different genetic characteristics of LuM and LiM from left-sided microsatellite stable CRC. METHODS Tissue samples of the primary tumors and paired metastases from 18 CRC patients with isolated LuM (LuM cohort), 18 patients with isolated LiM (LiM cohort), and 10 locally advanced CRC patients without metastases (control cohort) were selected for next-generation sequencing. Patients in the LiM cohort had matched clinicopathological characteristics with the LuM cohort. The single-nucleotide variations (SNVs), copy number variations (CNVs), pathway alterations, and tumor mutation burdens (TMBs) were also calculated and analyzed. RESULTS The CNV results showed that ZFHX4, GATA2, and FAM131B amplifications were more common in the metastatic cohorts than in the control cohort, while RECQL4 and FLCN amplifications were common in the controls. The LuM cohort had significantly higher proportions of HNF4A, BRD4, and U2AF1 amplification. The LuM, LiM, and control cohorts were successfully separated using pathway alteration analysis. The LuM cohort had more frequent alterations in the RTK/RAS pathway, HIPPO pathway, KRAS, and MET than the LiM group. The LuM cohort also had relatively higher TMBs than the LiM cohort. CONCLUSIONS CNVs in primary tumors could identify patients with LuM. Targeting the HIPPO pathway or MET and immune checkpoint inhibitors (ICIs) combined with other agents might be novel therapies for LuM.
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Affiliation(s)
- Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xue Zheng
- Genecast Biotechnology Co., Ltd., Wuxi, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yawei Chen
- Genecast Biotechnology Co., Ltd., Wuxi, China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianing Yu
- Genecast Biotechnology Co., Ltd., Wuxi, China
| | | | - Beibei Mao
- Genecast Biotechnology Co., Ltd., Wuxi, China
| | - Henghui Zhang
- Genecast Biotechnology Co., Ltd., Wuxi, China
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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11
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Lan YT, Chang SC, Lin PC, Lin CC, Lin HH, Huang SC, Lin CH, Liang WY, Chen WS, Jiang JK, Yang SH, Lin JK. Clinicopathological and molecular features between synchronous and metachronous metastases in colorectal cancer. Am J Cancer Res 2021; 11:1646-1658. [PMID: 33948379 PMCID: PMC8085873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/13/2021] [Indexed: 06/12/2023] Open
Abstract
The molecular difference between synchronous and metachronous metastases in colorectal cancer (CRC) remains unclear. Between 2000 and 2010, a total of 492 CRC patients were enrolled, including 280 with synchronous metastasis and 212 with metachronous metastasis. Clinicopathological and molecular features were compared between the two groups. Patients with synchronous metastasis were more likely to have right-sided CRC, poorly differentiated tumors, lymphovascular invasion, advanced pathological tumor (T) and node (N) categories, and liver metastases than those with metachronous metastasis. For right-sided CRC, patients with synchronous metastasis had more lymphovascular invasion and liver metastases than those with metachronous metastasis. For left-sided CRC, patients with synchronous metastasis were more likely to have poorly differentiated tumors, lymphovascular invasion, advanced pathological T and N categories, and liver metastases than those with metachronous metastasis. Regarding the genetic mutations, patients with metachronous metastasis had more mutations in TP53, NRAS, and HRAS and fewer mutations in APC than those with synchronous metastasis; for right-sided CRC, synchronous metastasis was associated with more APC mutations than metachronous metastasis, while for left-sided CRC, metachronous metastasis was associated with more TP53 and NRAS mutations than synchronous metastasis. The 5-year overall survival (OS) rates were significantly higher in metachronous metastasis patients than in synchronous metastasis patients, especially those with left-sided CRC. Multivariate analysis showed that age, sex, lymphovascular invasion, pathological N category, metachronous metastasis, and BRAF and NRAS mutations were independent prognostic factors affecting OS. CRC patients with synchronous metastasis had a worse OS than those with metachronous metastasis and exhibited distinct genetic mutations.
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Affiliation(s)
- Yuan-Tzu Lan
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Shih-Ching Chang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Pei-Ching Lin
- Department of Clinical Pathology, Yang-Ming Branch, Taipei City HospitalTaipei, Taiwan
- Department of Health and Welfare, University of TaipeiTaipei Taiwan
| | - Chun-Chi Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Hung-Hsin Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Shen-Chieh Huang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Chien-Hsing Lin
- Division of Genomic Medicine, National Health Research InstitutesZhunan, Taiwan
| | - Wen-Yi Liang
- Department of Pathology, Taipei Veterans General HospitalTaipei, Taiwan
| | - Wei-Shone Chen
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Jeng-Kai Jiang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Shung-Haur Yang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
- Department of Surgery, National Yang Ming Chiao Tung University HospitalYilan, Taiwan
| | - Jen-Kou Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General HospitalTaipei, Taiwan
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
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12
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Hoefflin R, Lazarou A, Hess ME, Reiser M, Wehrle J, Metzger P, Frey AV, Becker H, Aumann K, Berner K, Boeker M, Buettner N, Dierks C, Duque-Afonso J, Eisenblaetter M, Erbes T, Fritsch R, Ge IX, Geißler AL, Grabbert M, Heeg S, Heiland DH, Hettmer S, Kayser G, Keller A, Kleiber A, Kutilina A, Mehmed L, Meiss F, Poxleitner P, Rawluk J, Ruf J, Schäfer H, Scherer F, Shoumariyeh K, Tzschach A, Peters C, Brummer T, Werner M, Duyster J, Lassmann S, Miething C, Boerries M, Illert AL, von Bubnoff N. Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis. Cancers (Basel) 2021; 13:1151. [PMID: 33800365 PMCID: PMC7962829 DOI: 10.3390/cancers13051151] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/28/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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Affiliation(s)
- Rouven Hoefflin
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Adriana Lazarou
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Maria Elena Hess
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
| | - Meike Reiser
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Julius Wehrle
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Patrick Metzger
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
| | - Anna Verena Frey
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Heiko Becker
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Konrad Aumann
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Kai Berner
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Obstetrics and Gynaecology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Martin Boeker
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Medical Biometry and Statistics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Nico Buettner
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Medicine II, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Christine Dierks
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Jesus Duque-Afonso
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Michel Eisenblaetter
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Freiburg, Department of Radiology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Thalia Erbes
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Obstetrics and Gynaecology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ralph Fritsch
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Isabell Xiang Ge
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Obstetrics and Gynaecology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Anna-Lena Geißler
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Markus Grabbert
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Urology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Steffen Heeg
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Medicine II, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Dieter Henrik Heiland
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Neurosurgery, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Simone Hettmer
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Pediatric Hematology and Oncology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Gian Kayser
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Alexander Keller
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Anita Kleiber
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Alexandra Kutilina
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Leman Mehmed
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Clinical Cancer Registry, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Frank Meiss
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Dermatology and Venerology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Philipp Poxleitner
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Oral and Maxillofacial Surgery, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Justyna Rawluk
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Juri Ruf
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Nuclear Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Henning Schäfer
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Department of Neurosurgery, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Radiation Oncology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Florian Scherer
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
| | - Khalid Shoumariyeh
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andreas Tzschach
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute of Human Genetics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Christoph Peters
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Center for Biological Signaling Studies BIOSS, University of Freiburg, 79104 Freiburg, Germany
| | - Tilman Brummer
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Center for Biological Signaling Studies BIOSS, University of Freiburg, 79104 Freiburg, Germany
| | - Martin Werner
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Justus Duyster
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Silke Lassmann
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Center for Biological Signaling Studies BIOSS, University of Freiburg, 79104 Freiburg, Germany
| | - Cornelius Miething
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Melanie Boerries
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Anna L. Illert
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Nikolas von Bubnoff
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (R.H.); (A.L.); (J.W.); (H.B.); (C.D.); (J.D.-A.); (R.F.); (A.K.); (A.K.); (A.K.); (J.R.); (F.S.); (K.S.); (J.D.); (C.M.); (N.v.B.)
- Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (M.E.H.); (M.R.); (A.V.F.); (K.A.); (K.B.); (M.B.); (N.B.); (M.E.); (T.E.); (I.X.G.); (A.-L.G.); (M.G.); (S.H.); (D.H.H.); (S.H.); (G.K.); (L.M.); (F.M.); (P.P.); (J.R.); (H.S.); (A.T.); (C.P.); (T.B.); (M.W.); (S.L.); (M.B.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Schittenhelm J, Ziegler L, Sperveslage J, Mittelbronn M, Capper D, Burghardt I, Poso A, Biskup S, Skardelly M, Tabatabai G. FGFR3 overexpression is a useful detection tool for FGFR3 fusions and sequence variations in glioma. Neurooncol Pract 2020; 8:209-221. [PMID: 33898054 DOI: 10.1093/nop/npaa075] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background Fibroblast growth factor receptor (FGFR) inhibitors are currently used in clinical development. A subset of glioblastomas carries gene fusion of FGFR3 and transforming acidic coiled-coil protein 3. The prevalence of other FGFR3 alterations in glioma is currently unclear. Methods We performed RT-PCR in 101 glioblastoma samples to detect FGFR3-TACC3 fusions ("RT-PCR cohort") and correlated results with FGFR3 immunohistochemistry (IHC). Further, we applied FGFR3 IHC in 552 tissue microarray glioma samples ("TMA cohort") and validated these results in two external cohorts with 319 patients. Gene panel sequencing was carried out in 88 samples ("NGS cohort") to identify other possible FGFR3 alterations. Molecular modeling was performed on newly detected mutations. Results In the "RT-PCR cohort," we identified FGFR3-TACC3 fusions in 2/101 glioblastomas. Positive IHC staining was observed in 73/1024 tumor samples of which 10 were strongly positive. In the "NGS cohort," we identified FGFR3 fusions in 9/88 cases, FGFR3 amplification in 2/88 cases, and FGFR3 gene mutations in 7/88 cases in targeted sequencing. All FGFR3 fusions and amplifications and a novel FGFR3 K649R missense mutation were associated with FGFR3 overexpression (sensitivity and specificity of 93% and 95%, respectively, at cutoff IHC score > 7). Modeling of these data indicated that Tyr647, a residue phosphorylated as a part of FGFR3 activation, is affected by the K649R mutation. Conclusions FGFR3 IHC is a useful screening tool for the detection of FGFR3 alterations and could be included in the workflow for isocitrate dehydrogenase (IDH) wild-type glioma diagnostics. Samples with positive FGFR3 staining could then be selected for NGS-based diagnostic tools.
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Affiliation(s)
- Jens Schittenhelm
- Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Lukas Ziegler
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Jan Sperveslage
- Department of Pathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Michel Mittelbronn
- Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg.,Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.,National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg.,Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.,Edinger Institute (Neurological Institute), University of Frankfurt, Frankfurt, Germany
| | - David Capper
- Institute of Neuropathology, Berlin Institute of Health, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Isabel Burghardt
- Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Department of Neurology & Interdisciplinary Neurooncology, University Hospital Tübingen, Hertie-Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tuebingen, Germany
| | - Antti Poso
- Department of Internal Medicine VIII, University Hospital Tuebingen, Tuebingen, Germany
| | - Saskia Biskup
- CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, Germany
| | - Marco Skardelly
- Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Ghazaleh Tabatabai
- Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Department of Neurology & Interdisciplinary Neurooncology, University Hospital Tübingen, Hertie-Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tuebingen, Germany.,Center for Personalized Medicine, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,German Consortium for Translational Cancer Research (DKTK), DKFZ partner site Tuebingen, Tuebingen, Germany
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14
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Georgescu MM, Islam MZ, Li Y, Circu ML, Traylor J, Notarianni CM, Kline CN, Burns DK. Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma. Acta Neuropathol Commun 2020; 8:111. [PMID: 32680567 PMCID: PMC7367358 DOI: 10.1186/s40478-020-00992-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/18/2022] Open
Abstract
Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.
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15
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Zhang N, Di J, Wang Z, Gao P, Jiang B, Su X. Genomic profiling of colorectal cancer with isolated lung metastasis. Cancer Cell Int 2020; 20:281. [PMID: 32624706 PMCID: PMC7329491 DOI: 10.1186/s12935-020-01373-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/22/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Metastasis is a major cause of failed colorectal cancer (CRC) treatment. While lung metastasis (LM) is observed in 10-15% of patients with CRC, the genetic mechanisms that cause CRC to metastasize to the lung remain unclear. METHODS In this study, we employed whole exome sequencing (WES) of primary CRC tumors and matched isolated LM lesions to compare their genomic profiles. Comprehensive genomic analyses of five freshly frozen primary tumor lesions, five paired LM lesions, and matched non-cancerous tissues was achieved by WES. RESULTS An integrated analysis of somatic mutations, somatic copy number alterations, and clonal structures revealed that genomic alterations were present in primary and metastatic CRCs with various levels of discordance, indicating substantial levels of intertumor heterogeneity. Moreover, our results suggest that the founder clone of the primary tumor was responsible for the formation of the metastatic lesion. Additionally, only a few metastasis-specific mutations were identified, suggesting that LM-promoting mutations might be pre-existing in primary tumors. CONCLUSIONS Primary and metastatic CRC show intertumor heterogeneity; however, both lesions were founded by the same clone. These results indicate that malignant clones contributing to disease progression should be identified during the genetic prognosis of cancer metastasis.
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Affiliation(s)
- Nan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Jiabo Di
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Zaozao Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Pin Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Beihai Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
| | - Xiangqian Su
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142 China
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16
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Ottaiano A, Circelli L, Lombardi A, Scala S, Martucci N, Galon J, Buonanno M, Scognamiglio G, Botti G, Hermitte F, Savarese G, D'Amore L, Tatangelo F, Di Mauro A, Liguori G, Trotta AM, Napolitano M, Capozzi M, Tafuto S, Perri F, La Rocca A, Caraglia M, Nasti G. Genetic trajectory and immune microenvironment of lung-specific oligometastatic colorectal cancer. Cell Death Dis 2020; 11:275. [PMID: 32332709 PMCID: PMC7181838 DOI: 10.1038/s41419-020-2480-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/10/2020] [Accepted: 04/10/2020] [Indexed: 01/08/2023]
Abstract
Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.
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Affiliation(s)
- Alessandro Ottaiano
- Department of Abdominal Oncology, SSD-Innovative Therapies for Abdominal Cancers, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", , Via M. Semmola, 80131, Naples, Italy.
| | - Luisa Circelli
- AMES-Centro Polidiagnostico Strumentale, Srl, Naples, Italy
| | - Angela Lombardi
- Department of Precision Medicine, University of Campania "L. Vanvitelli" , Via L. De Crecchio, 7, 80138, Naples, Italy
| | - Stefania Scala
- Functional Genomics, Istituto Nazionale Tumori, IRCCS "G. Pascale" , Via M. Semmola, 80131, Naples, Italy
| | - Nicola Martucci
- Department of Thoracic Surgery and Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale" , Via M. Semmola, 80131, Naples, Italy
| | - Jerome Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre le Cancer, Sorbonne Université, Université Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Centre de Recherche des Cordeliers, 75006, Paris, France
| | - Manuela Buonanno
- Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, New York, New York, NY, USA
| | - Giosuè Scognamiglio
- Department of Pathology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale",, Via M. Semmola, 80131, Naples, Italy
| | - Gerardo Botti
- Department of Pathology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale",, Via M. Semmola, 80131, Naples, Italy
| | | | | | - Luigi D'Amore
- AMES-Centro Polidiagnostico Strumentale, Srl, Naples, Italy
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale",, Via M. Semmola, 80131, Naples, Italy
| | - Annabella Di Mauro
- Department of Pathology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale",, Via M. Semmola, 80131, Naples, Italy
| | - Giuseppina Liguori
- Department of Pathology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale",, Via M. Semmola, 80131, Naples, Italy
| | - Anna Maria Trotta
- Functional Genomics, Istituto Nazionale Tumori, IRCCS "G. Pascale" , Via M. Semmola, 80131, Naples, Italy
| | - Maria Napolitano
- Functional Genomics, Istituto Nazionale Tumori, IRCCS "G. Pascale" , Via M. Semmola, 80131, Naples, Italy
| | - Monica Capozzi
- Department of Abdominal Oncology, Clinical and Experimental Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - Salvatore Tafuto
- Department of Abdominal Oncology, Clinical and Experimental Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - Francesco Perri
- Head and Neck Cancer Medical Oncology Unit, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - Antonello La Rocca
- Department of Thoracic Surgery and Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale" , Via M. Semmola, 80131, Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "L. Vanvitelli" , Via L. De Crecchio, 7, 80138, Naples, Italy.,Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy
| | - Guglielmo Nasti
- Department of Abdominal Oncology, SSD-Innovative Therapies for Abdominal Cancers, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", , Via M. Semmola, 80131, Naples, Italy
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17
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Pappas-Gogos G, Baltagiannis EG, Kyrochristos ID, Ziogas DE, Goussia A, Mitsis M, Roukos DH. Predictive and patient-monitoring biomarkers: precision in the management of colorectal cancer. Biomark Med 2020; 14:335-339. [PMID: 32250157 DOI: 10.2217/bmm-2020-0025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Affiliation(s)
- Georgios Pappas-Gogos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | - Evangelos G Baltagiannis
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | - Ioannis D Kyrochristos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | - Demosthenes E Ziogas
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
- Department of Surgery, 'G Hatzikosta' General Hospital, Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, University Hospital of Ioannina, Ioannina, Greece
| | - Michail Mitsis
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | - Dimitrios H Roukos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
- Department of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
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18
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Kyrochristos ID, Ziogas DE, Goussia A, Glantzounis GK, Roukos DH. Bulk and Single-Cell Next-Generation Sequencing: Individualizing Treatment for Colorectal Cancer. Cancers (Basel) 2019; 11:1809. [PMID: 31752125 PMCID: PMC6895993 DOI: 10.3390/cancers11111809] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/24/2022] Open
Abstract
The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice to the innovative development of screening, predictive and therapeutic tools. Explosive integration of next-generation sequencing (NGS) systems into basic, translational and, more recently, basket trials is transforming biomedical and cancer research, aiming for substantial clinical implementation as well. Shifting from inter-patient tumor variability to the precise characterization of intra-tumor genetic, genomic and transcriptional heterogeneity (ITH) via multi-regional bulk tissue NGS and emerging single-cell transcriptomics, coupled with NGS of circulating cell-free DNA (cfDNA), unravels novel strategies for therapeutic response prediction and drug development. Remarkably, underway and future genomic/transcriptomic studies and trials exploring spatiotemporal clonal evolution represent most rational expectations to discover novel prognostic, predictive and therapeutic tools. This review describes latest advancements and future perspectives of integrated sequencing systems for genome and transcriptome exploration to overcome unmet research and clinical challenges towards Precision Oncology.
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Affiliation(s)
- Ioannis D. Kyrochristos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece; (I.D.K.); (D.E.Z.)
- Department of Surgery, Ioannina University Hospital, 45500 Ioannina, Greece;
| | - Demosthenes E. Ziogas
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece; (I.D.K.); (D.E.Z.)
- Department of Surgery, ‘G. Hatzikosta’ General Hospital, 45001 Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, Ioannina University Hospital, 45500 Ioannina, Greece;
| | | | - Dimitrios H. Roukos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece; (I.D.K.); (D.E.Z.)
- Department of Surgery, Ioannina University Hospital, 45500 Ioannina, Greece;
- Department of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
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19
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Kyrochristos ID, Roukos DH. Comprehensive intra-individual genomic and transcriptional heterogeneity: Evidence-based Colorectal Cancer Precision Medicine. Cancer Treat Rev 2019; 80:101894. [PMID: 31518831 DOI: 10.1016/j.ctrv.2019.101894] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 12/14/2022]
Abstract
Despite advances in translating conventional research into multi-modal treatment for colorectal cancer (CRC), therapeutic resistance and relapse remain unresolved in advanced resectable and, particularly, non-resectable disease. Genome and transcriptome sequencing and editing technologies, coupled with interaction mapping and machine learning, are transforming biomedical research, representing the most rational hope to overcome unmet research and clinical challenges. Rapid progress in both bulk and single-cell next-generation sequencing (NGS) analyses in the identification of primary and metastatic intratumor genomic and transcriptional heterogeneity (ITH) and the detection of circulating cell-free DNA (cfDNA) alterations is providing critical insight into the origins and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse. Moreover, DNA and RNA editing pave new avenues towards the discovery of novel drug targets. Breakthrough combinations of sequencing and editing systems with technologies exploring dynamic interaction networks within pioneering studies could delineate how coding and non-coding mutations perturb regulatory networks and gene expression. This review discusses latest data on genomic and transcriptomic landscapes in time and space, as well as early-phase clinical trials on targeted drug combinations, highlighting the transition from research to clinical Colorectal Cancer Precision Medicine, through non-invasive screening, individualized drug response prediction and development of multiple novel drugs. Future studies exploring the potential to target key transcriptional drivers and regulators will contribute to the next-generation pharmaceutical controllability of multi-layered aberrant transcriptional biocircuits.
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Affiliation(s)
- Ioannis D Kyrochristos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece; Department of Surgery, Ioannina University Hospital, Ioannina, Greece
| | - Dimitrios H Roukos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece; Department of Surgery, Ioannina University Hospital, Ioannina, Greece; Department of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
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20
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Lalonde E, Ebrahimzadeh J, Rafferty K, Richards-Yutz J, Grant R, Toorens E, Marie Rosado J, Schindewolf E, Ganguly T, Kalish JM, Deardorff MA, Ganguly A. Molecular diagnosis of somatic overgrowth conditions: A single-center experience. Mol Genet Genomic Med 2019; 7:e536. [PMID: 30761771 PMCID: PMC6418364 DOI: 10.1002/mgg3.536] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/02/2018] [Accepted: 12/02/2018] [Indexed: 01/24/2023] Open
Abstract
Background Somatic overgrowth conditions, including Proteus syndrome, Sturge–Weber syndrome, and PIK3CA‐related overgrowth spectrum, are caused by post‐zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth‐promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage. Methods We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8‐gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next‐generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×. Results Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post‐natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel. Conclusion Next‐generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis.
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Affiliation(s)
- Emilie Lalonde
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jessica Ebrahimzadeh
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Keith Rafferty
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jennifer Richards-Yutz
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Richard Grant
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Erik Toorens
- Penn Genomic Analysis Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jennifer Marie Rosado
- Penn Genomic Analysis Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Erica Schindewolf
- Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Tapan Ganguly
- Penn Genomic Analysis Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jennifer M Kalish
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Matthew A Deardorff
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Arupa Ganguly
- Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
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21
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Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O'Dwyer ST, Aziz O. Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine 2019; 40:363-374. [PMID: 30733075 PMCID: PMC6413540 DOI: 10.1016/j.ebiom.2019.01.050] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/13/2019] [Accepted: 01/24/2019] [Indexed: 12/17/2022] Open
Abstract
Background The use of biomarkers to target anti-EGFR treatments for metastatic colorectal cancer (CRC) is well-established, requiring molecular analysis of primary or metastatic biopsies. We aim to review concordance between primary CRC and its metastatic sites. Methods A systematic review and meta-analysis of all published studies (1991–2018) reporting on biomarker concordance between primary CRC and its metastatic site(s) was undertaken according to PRISMA guidelines using several medical databases. Studies without matched samples or using peripheral blood for biomarker analysis were excluded. Findings 61 studies including 3565 patient samples were included. Median biomarker concordance for KRAS (n = 50) was 93.7% [[67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100]], NRAS (n = 11) was 100% [[90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100]], BRAF (n = 22) was 99.4% [[80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100]], and PIK3CA (n = 17) was 93% [[42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100]]. Meta-analytic pooled discordance was 8% for KRAS (95% CI = 5–10%), 8% for BRAF (95% CI = 5–10%), 7% for PIK3CA (95% CI = 2–13%), and 28% overall (95% CI = 14–44%). The liver was the most commonly biopsied metastatic site (n = 2276), followed by lung (n = 438), lymph nodes (n = 1123), and peritoneum (n = 132). Median absolute concordance in multiple biomarkers was 81% (5–95%). Interpretation Metastatic CRC demonstrates high concordance across multiple biomarkers, suggesting that molecular testing of either the primary or liver and lung metastasis is adequate. More research on colorectal peritoneal metastases is required.
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Affiliation(s)
- D S Bhullar
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK
| | - J Barriuso
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK
| | - S Mullamitha
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK
| | - M P Saunders
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK
| | - S T O'Dwyer
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK
| | - O Aziz
- Colorectal & Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine and Health, University of Manchester, UK.
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22
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Singh V, Guleria P, Malik PS, Mohan A, Thulkar S, Pandey RM, Luthra K, Arava S, Ray R, Jain D. Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India. Curr Probl Cancer 2018; 43:391-401. [PMID: 30591192 DOI: 10.1016/j.currproblcancer.2018.12.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/13/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022]
Abstract
Mitogen-Activated Protein (MAP) Kinase pathway involves several oncogenic genes which can serve as potential targets for therapy. Therefore, aim of the present study is to analyze mutations in the MAP Kinase pathway in pulmonary adenocarcinoma (ADCA) of Indian patients along with clinico-pathologic correlation and determination of the survival status in patients receiving therapy. Blocks and slides of 125 pulmonary ADCA of last 5 years were retrieved. Histo-morphology and tumor content were determined. EGFR, KRAS, BRAF and MEK1 genes were analyzed using Sanger sequencing and Real-time polymerase chain reaction (PCR). Clinico-pathologic correlation and survival analysis were performed. Fifty-eight (46.4%) patients harbored genetic mutations of which 49 had single somatic mutations, 5 had multiple exonic and 4 showed coexisting EGFR and KRAS mutations. EGFR mutations were seen in 24.8%, KRAS in 19.2% and BRAF (non-V600E) in 2.4% cases. There was no difference in progression-free survival of wild- type/single mutations when compared with multiple/ coexisting mutations (P = 0.09). However, the P value may indicate borderline correlation. To conclude, EGFR and KRAS mutations may coexist in the same patient in lung ADCA. Multiple exonic mutations of KRAS gene formed substantial percentage of our cohort, requiring further exploration. Lung ADCA harbouring BRAF mutations are commonly non-V600E. Testing of all major genetic driver mutations of lung ADCA irrespective of histology and other demographic characteristics is necessary.
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Affiliation(s)
- Varsha Singh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Prerna Guleria
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Prabhat Singh Malik
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Anant Mohan
- Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences, New Delhi, India
| | - Sanjay Thulkar
- Department of Radio-Diagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - R M Pandey
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sudheer Arava
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ruma Ray
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Deepali Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
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23
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Molinari C, Marisi G, Passardi A, Matteucci L, De Maio G, Ulivi P. Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine? Int J Mol Sci 2018; 19:E3733. [PMID: 30477151 PMCID: PMC6321493 DOI: 10.3390/ijms19123733] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022] Open
Abstract
High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.
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Affiliation(s)
- Chiara Molinari
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Laura Matteucci
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giulia De Maio
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
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24
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Ziogas DE, Kyrochristos ID, Roukos DH. Discovering novel valid biomarkers and drugs in patient-centric genomic trials: the new epoch of precision surgical oncology. Drug Discov Today 2018; 23:1848-1872. [PMID: 30077778 DOI: 10.1016/j.drudis.2018.07.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/10/2018] [Accepted: 07/26/2018] [Indexed: 12/16/2022]
Abstract
Despite standardization of multimodal treatment and approval of several targeted drugs for resectable, non-metastatic cancer (M0 patients), intrinsic and acquired resistance and relapse rates remain high, even in early-stage aggressive tumors. Genome analysis could overcome these unmet needs. Our comprehensive review underlines the controversy on stable or spatiotemporally evolving clones as well as promising yet inconclusive data on genome-based biomarkers and drug development. We propose clinicogenomic trials in M0 patients for the validation of intratumor heterogeneity (ITH), circulating genomic subclones (cGSs) and intra-patient genomic heterogeneity (IPGH) as biomarkers and simultaneous discovery of novel oncotargets. This evidence-based strategy highlights the coming of precision surgical oncology with a future perspective of understanding and disrupting deregulated transcriptional networks.
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Affiliation(s)
- Demosthenes E Ziogas
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece; Department of Surgery, 'G. Hatzikosta' General Hospital, Ioannina, Greece
| | - Ioannis D Kyrochristos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece; Department of Surgery, Ioannina University Hospital, Ioannina, Greece
| | - Dimitrios H Roukos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece; Department of Surgery, Ioannina University Hospital, Ioannina, Greece; Department of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
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25
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Schweiger T, Liebmann-Reindl S, Glueck O, Starlinger P, Laengle J, Birner P, Klepetko W, Pils D, Streubel B, Hoetzenecker K. Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery. J Thorac Dis 2018; 10:6147-6157. [PMID: 30622786 DOI: 10.21037/jtd.2018.10.72] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease. Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables. Methods Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact. Results Mutations were found most frequently in APC, TP53 and KRAS, in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence (EGFR, GNAQ, KIT, MET, and PTPN11) and for overall survival (OS) (PDGFRA, SMARCB1, and TP53). Conclusions Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.
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Affiliation(s)
- Thomas Schweiger
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Sandra Liebmann-Reindl
- Core Facility Genomics, Comprehensive Cancer Center, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Olaf Glueck
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Johannes Laengle
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Peter Birner
- Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Dietmar Pils
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Institute of Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Berthold Streubel
- Core Facility Genomics, Comprehensive Cancer Center, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
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26
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Hoefflin R, Geißler AL, Fritsch R, Claus R, Wehrle J, Metzger P, Reiser M, Mehmed L, Fauth L, Heiland DH, Erbes T, Stock F, Csanadi A, Miething C, Weddeling B, Meiss F, von Bubnoff D, Dierks C, Ge I, Brass V, Heeg S, Schäfer H, Boeker M, Rawluk J, Botzenhart EM, Kayser G, Hettmer S, Busch H, Peters C, Werner M, Duyster J, Brummer T, Boerries M, Lassmann S, von Bubnoff N. Personalized Clinical Decision Making Through Implementation of a Molecular Tumor Board: A German Single-Center Experience. JCO Precis Oncol 2018; 2:PO.18.00105. [PMID: 32913998 PMCID: PMC7446498 DOI: 10.1200/po.18.00105] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Dramatic advances in our understanding of the molecular pathophysiology of cancer, along with a rapidly expanding portfolio of molecular targeted drugs, have led to a paradigm shift toward personalized, biomarker-driven cancer treatment. Here, we report the 2-year experience of the Comprehensive Cancer Center Freiburg Molecular Tumor Board (MTB), one of the first interdisciplinary molecular tumor conferences established in Europe. The role of the MTB is to recommend personalized therapy for patients with cancer beyond standard-of-care treatment. METHODS This retrospective case series includes 198 patients discussed from March 2015 through February 2017. The MTB guided individual molecular diagnostics, assessed evidence of actionability of molecular alterations, and provided therapy recommendations, including approved and off-label treatments as well as available matched clinical trials. RESULTS The majority of patients had metastatic solid tumors (73.7%), mostly progressive (77.3%) after a mean of 2.0 lines of standard treatment. Diagnostic recommendations resulted in 867 molecular diagnostic tests for 172 patients (five per case), including exome analysis in 36 cases (18.2%). With a median turnaround time of 28 days, treatment recommendations were given to 104 patients (52.5%). These included single-agent targeted therapies (42.3%), checkpoint inhibitors (37.5%), and combination therapies (18.3%). Treatment recommendations were implemented in 33 of 104 patients (31.7%), of whom 19 (57.6%) showed stable disease or partial response, including 14 patients (7.1% of the entire population) receiving off-label treatments. CONCLUSION Personalized extended molecular-guided patient care is effective for a small but clinically meaningful proportion of patients in challenging clinical situations. Limited access to targeted drugs, lack of trials, and submission at late disease stage prevents broader applicability, whereas genome-wide analyses are not a strict requirement for predictive molecular testing.
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Affiliation(s)
- Rouven Hoefflin
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Anna-Lena Geißler
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Ralph Fritsch
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Rainer Claus
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Julius Wehrle
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Patrick Metzger
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Meike Reiser
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Leman Mehmed
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Lisa Fauth
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Dieter Henrik Heiland
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Thalia Erbes
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Friedrich Stock
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Agnes Csanadi
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Cornelius Miething
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Britta Weddeling
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Frank Meiss
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Dagmar von Bubnoff
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Christine Dierks
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Isabell Ge
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Volker Brass
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Steffen Heeg
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Henning Schäfer
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Martin Boeker
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Justyna Rawluk
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Elke Maria Botzenhart
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Gian Kayser
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Simone Hettmer
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Hauke Busch
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Christoph Peters
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Martin Werner
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Justus Duyster
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Tilman Brummer
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Melanie Boerries
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Silke Lassmann
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
| | - Nikolas von Bubnoff
- All authors: University of Freiburg, Freiburg; Ralph Fritsch, Julius Wehrle, Cornelius Miething, Christoph Peters, Martin Werner, Justus Duyster, Tilman Brummer, Melanie Boerries, Silke Lassmann, and Nikolas von Bubnoff, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; Rainer Claus, Augsburg Medical Center, Augsburg; and Hauke Busch, University of Lübeck, Lübeck, Germany
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27
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Yeh CH, Bellon M, Nicot C. FBXW7: a critical tumor suppressor of human cancers. Mol Cancer 2018; 17:115. [PMID: 30086763 PMCID: PMC6081812 DOI: 10.1186/s12943-018-0857-2] [Citation(s) in RCA: 371] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 07/16/2018] [Indexed: 12/14/2022] Open
Abstract
The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.
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Affiliation(s)
- Chien-Hung Yeh
- Department of Pathology and Laboratory Medicine, Center for Viral Pathogenesis, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Marcia Bellon
- Department of Pathology and Laboratory Medicine, Center for Viral Pathogenesis, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Christophe Nicot
- Department of Pathology and Laboratory Medicine, Center for Viral Pathogenesis, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
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28
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Mirza-Aghazadeh-Attari M, Darband SG, Kaviani M, Mihanfar A, Aghazadeh Attari J, Yousefi B, Majidinia M. DNA damage response and repair in colorectal cancer: Defects, regulation and therapeutic implications. DNA Repair (Amst) 2018; 69:34-52. [PMID: 30055507 DOI: 10.1016/j.dnarep.2018.07.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/15/2018] [Accepted: 07/15/2018] [Indexed: 12/11/2022]
Abstract
DNA damage response, a key factor involved in maintaining genome integrity and stability, consists of several kinase-dependent signaling pathways, which sense and transduce DNA damage signal. The severity of damage appears to determine DNA damage responses, which can include cell cycle arrest, damage repair and apoptosis. A number of recent studies have demonstrated that defection in signaling through this network is thought to be an underlying mechanism behind the development and progression of various types of human malignancies, including colorectal cancer. In this review, colorectal cancer and its molecular pathology as well as DNA damage response is briefly introduced. Finally, the involvement of key components of this network in the initiation/progression, prognosis, response to treatment and development of drug resistance is comprehensively discussed.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saber Ghazizadeh Darband
- Danesh Pey Hadi Co., Health Technology Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Ainaz Mihanfar
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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29
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Kastrisiou M, Zarkavelis G, Kampletsas E, Panopoulou E, Goussia A, Nasioulas G, Papadopoulou E, Tsaousi C, Pentheroudakis G. Clonal evolution of colorectal cancer in a patient with serially resected metastases and liquid biopsies: a case report and discussion of the literature. ESMO Open 2018; 3:e000329. [PMID: 29942663 PMCID: PMC6012565 DOI: 10.1136/esmoopen-2018-000329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 01/13/2023] Open
Abstract
Background Metastatic colorectal cancer represents a striking example of clonal heterogeneity and tumour evolution, which generates acquired resistance to therapy. Once hard to perform, the study of clonal heterogeneity is now significantly aided by the use of liquid biopsies. Method We herein report a case of a patient with colorectal cancer and serial development of multiple metastases which were all resected and genotyped. A rare point mutation was identified in the primary tumour (but not in any of the organ metastatic sites), as well as in the first and the last out of three consecutive liquid biopsies. The review of the literature offered some insight in the evolution of the patient’s tumour and general directions on how to interpret liquid biopsy results. Conclusions This patient case emphasises the need for large prospective studies designed to bridge liquid biopsy data with useful clinical endpoints, in order to optimally integrate this revolutionary tool in everyday practice.
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Affiliation(s)
- Myrto Kastrisiou
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.,Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
| | - George Zarkavelis
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.,Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
| | | | - Eleni Panopoulou
- Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece
| | | | | | - Christina Tsaousi
- Haematology Laboratory, Ioannina University Hospital, Ioannina, Greece
| | - George Pentheroudakis
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.,Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece
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30
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Le UT, Bronsert P, Picardo F, Riethdorf S, Haager B, Rylski B, Czerny M, Beyersdorf F, Wiesemann S, Pantel K, Passlick B, Kaifi JT, Schmid S. Intraoperative detection of circulating tumor cells in pulmonary venous blood during metastasectomy for colorectal lung metastases. Sci Rep 2018; 8:8751. [PMID: 29884810 PMCID: PMC5993733 DOI: 10.1038/s41598-018-26410-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/10/2018] [Indexed: 01/15/2023] Open
Abstract
Circulating tumor cells (CTC) have been studied extensively in various tumor types and are a well-established prognosticator in colorectal cancer (CRC). This is the first study to isolate CTC directly from the tumor outflow in secondary lung tumors. For this purpose in 24 patients with CRC who underwent pulmonary metastasectomy in curative intent blood was drawn intraoperatively from the pulmonary vein (tumor outflow). In 22 samples CTC-enumeration was performed using CellSieve-microfilters and immunohistochemical- and Giemsa-staining. Additionally 10 blood samples were analyzed using the CellSearch-System. We could isolate more CTC in pulmonary venous blood (total 41, range 0-15) than in samples taken from the periphery at the same time (total 6, range 0-5, p = 0.09). Tumor positive lymph nodes correlated with presence of CTC in pulmonary venous blood as in all cases CTC were present (p = 0.006). Our findings suggest a tumor cell release from pulmonary metastases in CRC and a correlation of CTC isolated from the tumor outflow with established negative prognostic markers in metastasized CRC. The presented data warrant further investigations regarding the significance of local tumor compartments when analyzing circulating markers and the possibility of tumor cell shedding from secondary lung tumors.
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Affiliation(s)
- Uyen-Thao Le
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Bronsert
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Francesco Picardo
- Laboratory of Molecular Medicine and Biotechnology, Campus Bio-Medico University of Rome, Rome, Italy
- Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Riethdorf
- Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benedikt Haager
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bartosz Rylski
- Department of Cardiovascular Surgery, University Heart Center Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Martin Czerny
- Department of Cardiovascular Surgery, University Heart Center Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Friedhelm Beyersdorf
- Department of Cardiovascular Surgery, University Heart Center Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sebastian Wiesemann
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Klaus Pantel
- Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bernward Passlick
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Jussuf Thomas Kaifi
- Section for Thoracic Surgery, Hugh E. Stephenson Jr., MD, Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, USA
| | - Severin Schmid
- Department of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany.
- Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Freiburg, Germany.
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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31
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De Mattos-Arruda L, Ng CKY, Piscuoglio S, Gonzalez-Cao M, Lim RS, De Filippo MR, Fusco N, Schultheis AM, Ortiz C, Viteri S, Arias A, Macedo GS, Oliveira M, Gomez P, Teixidó C, Nuciforo P, Peg V, Saura C, Ramon Y Cajal S, Casas FT, Weigelt B, Cortes J, Seoane J, Reis-Filho JS. Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases. Oncotarget 2018; 9:20617-20630. [PMID: 29755676 PMCID: PMC5945519 DOI: 10.18632/oncotarget.25041] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 03/12/2018] [Indexed: 12/19/2022] Open
Abstract
Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.
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Affiliation(s)
- Leticia De Mattos-Arruda
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Charlotte K Y Ng
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Institute of Pathology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Salvatore Piscuoglio
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | | | - Raymond S Lim
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria R De Filippo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nicola Fusco
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anne M Schultheis
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carolina Ortiz
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Alexandra Arias
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Gabriel S Macedo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mafalda Oliveira
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Patricia Gomez
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Vicente Peg
- Vall d'Hebron Institute of Research, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cristina Saura
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Santiago Ramon Y Cajal
- Vall d'Hebron Institute of Research, Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Javier Cortes
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain.,Ramon y Cajal University Hospital, Madrid, Spain
| | - Joan Seoane
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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32
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Cheng J, Song X, Ao L, Chen R, Chi M, Guo Y, Zhang J, Li H, Zhao W, Guo Z, Wang X. Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors. J Cancer 2018; 9:1500-1505. [PMID: 29721060 PMCID: PMC5929095 DOI: 10.7150/jca.23017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 01/27/2018] [Indexed: 12/21/2022] Open
Abstract
Background & Aims: Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified “liver-specific” genes whose expression levels ranked among the bottom 10% (“unexpressed”) of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5, were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P < 0.05). Genes co-expressed with ANGPTL3 and CFHR5 were significantly enriched in metabolism pathways characterizing liver tissues, including “starch and sucrose metabolism” and “drug metabolism-cytochrome P450”. Conclusions: For primary CRC with liver metastasis, both the liver metastases and corresponding primary colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.
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Affiliation(s)
- Jun Cheng
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Xuekun Song
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, China
| | - Lu Ao
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Rou Chen
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Meirong Chi
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - You Guo
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Jiahui Zhang
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Hongdong Li
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Wenyuan Zhao
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, China
| | - Zheng Guo
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China.,Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, 350122, China
| | - Xianlong Wang
- Fujian Key Laboratory of Medical Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
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33
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Hirsch B, Endris V, Lassmann S, Weichert W, Pfarr N, Schirmacher P, Kovaleva V, Werner M, Bonzheim I, Fend F, Sperveslage J, Kaulich K, Zacher A, Reifenberger G, Köhrer K, Stepanow S, Lerke S, Mayr T, Aust DE, Baretton G, Weidner S, Jung A, Kirchner T, Hansmann ML, Burbat L, von der Wall E, Dietel M, Hummel M. Multicenter validation of cancer gene panel-based next-generation sequencing for translational research and molecular diagnostics. Virchows Arch 2018; 472:557-565. [PMID: 29374318 PMCID: PMC5924673 DOI: 10.1007/s00428-017-2288-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 12/05/2017] [Accepted: 12/19/2017] [Indexed: 12/12/2022]
Abstract
The simultaneous detection of multiple somatic mutations in the context of molecular diagnostics of cancer is frequently performed by means of amplicon-based targeted next-generation sequencing (NGS). However, only few studies are available comparing multicenter testing of different NGS platforms and gene panels. Therefore, seven partner sites of the German Cancer Consortium (DKTK) performed a multicenter interlaboratory trial for targeted NGS using the same formalin-fixed, paraffin-embedded (FFPE) specimen of molecularly pre-characterized tumors (n = 15; each n = 5 cases of Breast, Lung, and Colon carcinoma) and a colorectal cancer cell line DNA dilution series. Detailed information regarding pre-characterized mutations was not disclosed to the partners. Commercially available and custom-designed cancer gene panels were used for library preparation and subsequent sequencing on several devices of two NGS different platforms. For every case, centrally extracted DNA and FFPE tissue sections for local processing were delivered to each partner site to be sequenced with the commercial gene panel and local bioinformatics. For cancer-specific panel-based sequencing, only centrally extracted DNA was analyzed at seven sequencing sites. Subsequently, local data were compiled and bioinformatics was performed centrally. We were able to demonstrate that all pre-characterized mutations were re-identified correctly, irrespective of NGS platform or gene panel used. However, locally processed FFPE tissue sections disclosed that the DNA extraction method can affect the detection of mutations with a trend in favor of magnetic bead-based DNA extraction methods. In conclusion, targeted NGS is a very robust method for simultaneous detection of various mutations in FFPE tissue specimens if certain pre-analytical conditions are carefully considered.
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Affiliation(s)
- B Hirsch
- Campus Mitte, Institute of Pathology, Charité-University Medicine Berlin, Virchowweg 15, 10117, Berlin, Germany. .,German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
| | - V Endris
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Medicine Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - S Lassmann
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Breisacherstraße 115A, 79106, Freiburg, Germany
| | - W Weichert
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, Technical University Munich (TUM), Munich, Germany
| | - N Pfarr
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, Technical University Munich (TUM), Munich, Germany
| | - P Schirmacher
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Medicine Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - V Kovaleva
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Breisacherstraße 115A, 79106, Freiburg, Germany
| | - M Werner
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Breisacherstraße 115A, 79106, Freiburg, Germany
| | - I Bonzheim
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology and Neuropathology, University Hospital Tuebingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - F Fend
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology and Neuropathology, University Hospital Tuebingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - J Sperveslage
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology and Neuropathology, University Hospital Tuebingen, Eberhard-Karls-University, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - K Kaulich
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Department of Neuropathology, Heinrich Heine University Duesseldorf and Biological and Medical Research Center (BMFZ), Genomics and Transcriptomics Laboratory, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
| | - A Zacher
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Department of Neuropathology, Heinrich Heine University Duesseldorf and Biological and Medical Research Center (BMFZ), Genomics and Transcriptomics Laboratory, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
| | - G Reifenberger
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Department of Neuropathology, Heinrich Heine University Duesseldorf and Biological and Medical Research Center (BMFZ), Genomics and Transcriptomics Laboratory, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
| | - K Köhrer
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Department of Neuropathology, Heinrich Heine University Duesseldorf and Biological and Medical Research Center (BMFZ), Genomics and Transcriptomics Laboratory, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
| | - S Stepanow
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Department of Neuropathology, Heinrich Heine University Duesseldorf and Biological and Medical Research Center (BMFZ), Genomics and Transcriptomics Laboratory, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany
| | - S Lerke
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - T Mayr
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - D E Aust
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - G Baretton
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - S Weidner
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, Ludwig-Maximilians University Munich, Thalkirchner Straße 36, 80337, Munich, Germany
| | - A Jung
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, Ludwig-Maximilians University Munich, Thalkirchner Straße 36, 80337, Munich, Germany
| | - T Kirchner
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Institute of Pathology, Ludwig-Maximilians University Munich, Thalkirchner Straße 36, 80337, Munich, Germany
| | - M L Hansmann
- German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Dr. Senckenberg Institute of Pathology, University Hospital, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - L Burbat
- Campus Mitte, Institute of Pathology, Charité-University Medicine Berlin, Virchowweg 15, 10117, Berlin, Germany.,German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - E von der Wall
- Campus Mitte, Institute of Pathology, Charité-University Medicine Berlin, Virchowweg 15, 10117, Berlin, Germany.,German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - M Dietel
- Campus Mitte, Institute of Pathology, Charité-University Medicine Berlin, Virchowweg 15, 10117, Berlin, Germany.,German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - M Hummel
- Campus Mitte, Institute of Pathology, Charité-University Medicine Berlin, Virchowweg 15, 10117, Berlin, Germany.,German Cancer Consortium (DKTK) Partner Site, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
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Wang Z, Wang X, Yuan J, Zhang X, Zhou J, Lu M, Liu D, Li J, Shen L. Survival Benefit of Palliative Local Treatments and Efficacy of Different Pharmacotherapies in Colorectal Cancer With Lung Metastasis: Results From a Large Retrospective Study. Clin Colorectal Cancer 2017; 17:e233-e255. [PMID: 29305209 DOI: 10.1016/j.clcc.2017.12.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/07/2017] [Indexed: 01/04/2023]
Abstract
BACKGROUND For most colorectal cancer patients with initial lung metastasis (LM), the only suitable treatments are palliative, including palliative local therapy and pharmacotherapy. We investigated the role of palliative local treatments in prolonging survival and the efficacy of different pharmacotherapies. PATIENTS AND METHODS After performing a medical record review of 2233 patients with metastatic colorectal cancer, 684 were identified as having LM. Their clinicopathologic characteristics, treatment patterns, and outcomes were analyzed retrospectively. RESULTS For nonresectable initial LM, patients receiving palliative local therapy had significantly longer median progression-free survival (PFS) and overall survival (OS) than those treated with pharmacotherapy alone: PFS 16.1 months versus 7.4 months (P < .001) and OS 51.8 months versus 23.8 months (P < .001), respectively. Cox multivariate analysis confirmed the survival benefit induced by palliative local therapy. Chemonaive patients receiving single-agent fluoropyrimidine had shorter PFS and longer OS compared to oxaliplatin- or irinotecan-based doublets when used as first-line treatment (PFS 4.8, 7.4, and 7.3 months; and OS 28.7, 21.2, and 20.1 months, respectively); however, these differences were not statistically significant. The addition of targeted agents to cytotoxic drugs prolonged PFS (10.5 vs. 7.2 months, P = .005) but not OS (27.8 vs. 21.2 months, P = .454). Carcinoembryonic antigen level, LM-associated symptoms, extrapulmonary disease, and histopathologic type were independent pretreatment prognostic factors. CONCLUSION Local treatments of LM may confer a survival benefit in the palliative setting. First-line single-agent fluoropyrimidine may be used in patients with good prognosis.
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Affiliation(s)
- Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jiajia Yuan
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Dan Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
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35
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Baicalein inhibits cervical cancer progression via downregulating long noncoding RNA BDLNR and its downstream PI3K/Akt pathway. Int J Biochem Cell Biol 2017; 94:107-118. [PMID: 29175387 DOI: 10.1016/j.biocel.2017.11.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/21/2017] [Accepted: 11/22/2017] [Indexed: 12/29/2022]
Abstract
Baicalein, an active flavonoid extracted from the root of Scutellaria baicalensis Georgi, has fascinating anti-cancer effects on many cancers. Our previous study also found that baicalein inhibited cervical cancer cell proliferation and migration, and induced cervical cancer cell apoptosis and cell cycle arrest. However, the molecular mechanisms underlying the anti-cancer effects of baicalein are largely unknown. In this study, we identified a novel long noncoding RNA (lncRNA), which is downregulated by baicalein in a dose- and time-dependent manner in cervical cancer. We named this lncRNA as baicalein down-regulated long noncoding RNA (BDLNR). Gain-of- and loss-of-function assays showed that BDLNR was required for baicalein-induced cell proliferation inhibition, cell death induction, migration inhibition, and in vivo tumor growth inhibition of cervical cancer. Mechanistically, BDLNR physically bound to YBX1, recruited YBX1 to PIK3CA promoter, activated PIK3CA expression and PI3K/Akt pathway. Furthermore, BDLNR was upregulated in cervical cancer and associated with poor prognosis of cervical cancer patients. Collectively, our data demonstrated that BDLNR mediated the anti-cancer effects of baicalein in cervical cancer via activating PI3K/Akt pathway, and implied that BDLNR would be potential therapeutic target for enhancing the anti-cancer effects of baicalein in cervical cancer.
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36
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Geißler AL, Geißler M, Kottmann D, Lutz L, Fichter CD, Fritsch R, Weddeling B, Makowiec F, Werner M, Lassmann S. ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer. Oncotarget 2017; 8:17164-17190. [PMID: 28199979 PMCID: PMC5370031 DOI: 10.18632/oncotarget.15211] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/16/2017] [Indexed: 12/23/2022] Open
Abstract
EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.
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Affiliation(s)
- Anna-Lena Geißler
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Miriam Geißler
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Daniel Kottmann
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Lisa Lutz
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Christiane D Fichter
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Ralph Fritsch
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Department of Internal Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Britta Weddeling
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Frank Makowiec
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Department of Surgery, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Martin Werner
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Silke Lassmann
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany
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37
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Zhou Y, Tian T, Zhu Y, Jaffar Ali D, Hu F, Qi Y, Sun B, Xiao Z. Exosomes Transfer Among Different Species Cells and Mediating miRNAs Delivery. J Cell Biochem 2017; 118:4267-4274. [PMID: 28422319 DOI: 10.1002/jcb.26077] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 04/18/2017] [Indexed: 12/18/2022]
Abstract
Exosomes, the natural vehicles of intercellular communication, transfer proteins, mRNAs, and microRNAs (miRNAs) and mediate many physiological and pathological processes. It is not clear that whether exosomal miRNAs could regulate gene expression across species, though some studies suggest interactions of exosomal miRNAs between cells. In this report, we have isolated exosomes from rat PC12 cells and assessed their internalization by human cancer Hela cells. The internalized exosomes were located in Hela lysosomes. Human PTEN expression was significantly deregulated due to miR-21 delivered by rat cell exosomes. Our results prove that exosomes could incorporate between cells of different species and could regulate the protein expressions in the recipient cells by delivering the enclosed miRNAs. Thus our study foreshadows a futuristic treatment approach of utilizing miRNA enclosed exosome vehicles sans species concerns in combating various diseases/ regulating abnormal proteins. J. Cell. Biochem. 118: 4267-4274, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Yueyuan Zhou
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Tian Tian
- Department of Neurobiology, Nanjing Medical University, 101 Longmian Avenu, Nanjing, 211166, China
| | - Yanliang Zhu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Doulathunnisa Jaffar Ali
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Feihu Hu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Yuhua Qi
- Key Laboratories of Enteric Pathogenic Microbiology, Ministry of Health, Microbiological Laboratory, Jiangsu Center for Disease Prevention and Control (CDC), 172 Jiangsu Rd, Nanjing, 210009, China
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Zhongdang Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
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38
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Kreisel W, Ruf G, Salm R, Lazaro A, Bengsch B, Globig AM, Fisch P, Lassmann S, Schmitt-Graeff A. Protein-losing pseudomembranous colitis with cap polyposis-like features. World J Gastroenterol 2017; 23:3003-3010. [PMID: 28522919 PMCID: PMC5413796 DOI: 10.3748/wjg.v23.i16.3003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/11/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
Protein-losing enteropathy (PLE) is characterized by loss of serum proteins into the gastrointestinal tract. It may lead to hypoproteinemia and clinically present as protein deficiency edema, ascites, pleural or pericardial effusion and/or malnutrition. In most cases the site of protein loss is the small intestine. Here we present an unusual case of severe PLE in a 55-year old female with a one-year history of recurrent diarrhea, crampy abdominal pain, and peripheral edema. Endoscopy and MRI showed a diffuse inflammatory thickening of the sigmoid colon and the rectum. Surgical resection of the involved colon was performed and the symptoms were significantly resolved. The final histologic evaluation confirmed a diagnosis of a pseudomembranous colitis with cap polyposis-like features. Such a cause of PLE has never been described before.
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39
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Ng CKY, Bidard FC, Piscuoglio S, Geyer FC, Lim RS, de Bruijn I, Shen R, Pareja F, Berman SH, Wang L, Pierga JY, Vincent-Salomon A, Viale A, Norton L, Sigal B, Weigelt B, Cottu P, Reis-Filho JS. Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases. Clin Cancer Res 2017; 23:4402-4415. [PMID: 28351929 DOI: 10.1158/1078-0432.ccr-16-3115] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 01/17/2017] [Accepted: 03/22/2017] [Indexed: 12/21/2022]
Abstract
Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy.Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods.Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA, and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2, and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases.Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. Clin Cancer Res; 23(15); 4402-15. ©2017 AACR.
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Affiliation(s)
- Charlotte K Y Ng
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Francois-Clement Bidard
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. .,Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France
| | - Salvatore Piscuoglio
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Felipe C Geyer
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil
| | - Raymond S Lim
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ino de Bruijn
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronglai Shen
- Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Fresia Pareja
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samuel H Berman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lu Wang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jean-Yves Pierga
- Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.,University Paris Descartes, Paris, France
| | | | - Agnes Viale
- Integrated Genomics Operations, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Larry Norton
- Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Brigitte Sigal
- Department of Pathology, Institut Curie, PSL Research University, Paris, France
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Paul Cottu
- Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. .,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
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