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Jesinghaus M. [Neuroendocrine carcinomas of the gastrointestinal tract : Morphology, molecular pathology, cellular origin]. PATHOLOGIE (HEIDELBERG, GERMANY) 2024; 45:8-13. [PMID: 39535611 DOI: 10.1007/s00292-024-01386-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024]
Abstract
Neuroendocrine carcinomas (NEC) are poorly differentiated neuroendocrine neoplasms that can occur ubiquitously in the mucosa-bearing organs of the gastrointestinal tract. Based on their morphology, they are classified into large cell (LCNEC) and small cell NEC (SCNEC). The most common form of mixed differentiation is the combination with an adenocarcinoma, referred to as mixed adenoneuroendocrine carcinoma (MANEC). NEC/MANEC exhibit a significantly poorer prognosis than the adenocarcinomas of their respective primary sites, which is inextricably linked to their typical histomorphology. Adenocarcinomas with aberrant expression of neuroendocrine markers do not show a worse clinical course. Molecularly, NEC/MANEC have a profile comparable to the adenocarcinomas of their site of origin and a profile divergent from neuroendocrine tumors. Analyses of gastric NEC/MANEC have shown frequent MYC amplifications, which are reflected in MYC signatures in various transcriptome analyses.The cellular origin of NEC remains a subject of controversial discussion. New insights are provided by a MYC-driven, genetically modified mouse model that led to the development of large gastric tumors. These tumors were histologically identified as LCNEC and were accompanied by both neuroendocrine and non-neuroendocrine precursor lesions. Using immunofluorescence, a derivation from resident neuroendocrine cells in the gastric corpus was demonstrated, suggesting that at least a portion of LCNEC may originate directly from neuroendocrine cells.
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Affiliation(s)
- Moritz Jesinghaus
- Institut für Pathologie, Philipps-Universität Marburg und Universitätsklinikum Gießen und Marburg, Standort Marburg, Marburg, Deutschland.
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Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance. J Clin Med 2021; 10:jcm10112458. [PMID: 34206061 PMCID: PMC8198627 DOI: 10.3390/jcm10112458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 11/17/2022] Open
Abstract
Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.
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Schank TE, Forschner A, Sachse MM, Dimitrakopoulou-Strauss A, Sachpekidis C, Stenzinger A, Volckmar AL, Enk A, Hassel JC. Complete Metabolic Response in FDG-PET-CT Scan before Discontinuation of Immune Checkpoint Inhibitors Correlates with Long Progression-Free Survival. Cancers (Basel) 2021; 13:cancers13112616. [PMID: 34073477 PMCID: PMC8198795 DOI: 10.3390/cancers13112616] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/15/2021] [Accepted: 05/21/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Immunotherapy is the standard of care in patients harboring metastasized melanoma. However, once further tumor growth is stopped it remains unclear when immunotherapy can be safely ceased. This clinical question is increasingly raised especially in patients with a strong desire to discontinue therapy or in patients who are forced to pause treatment due to severe immune-related side effects. With our study we aim to provide data which may be helpful for clinicians and patients when treatment discontinuation is considered. Further prospective, multicenter studies are needed to further address this important clinical issue. Abstract Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1–42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1–70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032–0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued.
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Affiliation(s)
- Timo E. Schank
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; (A.E.); (J.C.H.)
- Correspondence:
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany;
| | - Michael Max Sachse
- Department of Dermatology, Allergology, and Phlebology, Hospital Bremerhaven Reinkenheide, 27574 Bremerhaven, Germany;
| | | | - Christos Sachpekidis
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120 Heidelberg, Germany; (A.D.-S.); (C.S.)
| | - Albrecht Stenzinger
- Department of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (A.S.); (A.-L.V.)
| | - Anna-Lena Volckmar
- Department of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (A.S.); (A.-L.V.)
| | - Alexander Enk
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; (A.E.); (J.C.H.)
| | - Jessica C. Hassel
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; (A.E.); (J.C.H.)
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Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases. Am J Surg Pathol 2021; 45:969-978. [PMID: 34105518 DOI: 10.1097/pas.0000000000001692] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022]
Abstract
The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs. high), tumor budding (Bd1/Bd2/Bd3), and CRC subtype (adenocarcinoma not otherwise specified, micropapillary, mucinous, serrated, medullary, adenoma-like, signet-ring cell, mixed adenoneuroendocrine carcinoma/neuroendocrine carcinoma, undifferentiated) according to the criteria of the 2019 WHO classification. We investigated the interaction of these parameters, their connection to stage/microsatellite status, and their significance for patient survival in the different subgroups. Specific subtypes other than adenocarcinoma not otherwise specified represented one third of all CRCs and were unevenly distributed throughout stage and microsatellite subgroups. Subtypes, WHO grade and tumor budding profoundly impacted all survival parameters (P<0.001 for all analyses), with CRC subtypes and tumor budding-but not WHO grade-being stage-independent prognosticators for all survival comparisons. WHO grade had very limited prognostic value in CRC subtypes, while tumor budding retained its strong prognostic impact in most scenarios. Accurate delineation of CRC subtypes introduced in the 2019 WHO classification provides strong stage-independent prognostic information, arguing that they should be considered in pathology reports and in clinical trials. Of the morphology-based grading schemes included in the 2019 WHO, tumor budding outperforms WHO grade.
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Huang F, Tanaka H, Knudsen BS, Rutgers JK. Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to the favorable survival of patients with tumors with POLE mutations outside the exonuclease domain. BMC MEDICAL GENETICS 2020; 21:167. [PMID: 32838755 PMCID: PMC7446057 DOI: 10.1186/s12881-020-01089-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 07/08/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mutations in the exonuclease domain of POLE, a DNA polymerase associated with DNA replication and repair, lead to cancers with ultra-high mutation rates. Most studies focus on intestinal and uterine cancers with POLE mutations. These cancers exhibit a significant immune cell infiltrate and favorable prognosis. We questioned whether loss of function of other DNA polymerases can cooperate to POLE to generate the ultramutator phenotype. METHODS We used cases and data from 15 cancer types in The Cancer Genome Atlas to investigate mutation frequencies of 14 different DNA polymerases. We tested whether tumor mutation burden, patient outcome (disease-free survival) and immune cell infiltration measured by ESTIMATE can be attributed to mutations in POLQ and POLZ/REV3L. RESULTS Thirty six percent of colorectal, stomach and endometrial cancers with POLE mutations carried additional mutations in POLQ (E/Q), POLZ/REV3L (E/Z) or both DNA polymerases (E/Z/Q). The mutation burden in these tumors was significantly greater compared to POLE-only (E) mutant tumors (p < 0.001). In addition, E/Q, E/Z, and E/Q/Z mutant tumors possessed an increased frequency of mutations in the POLE exonuclease domain (p = 0.013). Colorectal, stomach and endometrial E/Q, E/Z, and E/Q/Z mutant tumors within TCGA demonstrated 100% disease-free survival, even if the POLE mutations occurred outside the exonuclease domain (p = 0.003). However, immune scores in these tumors were related to microsatellite instability (MSI) and not POLE mutation status. This suggests that the host immune response may not be the sole mechanism for prolonged disease-free survival of ultramutated tumors in this cohort. CONCLUSION Results in this study demonstrate that mutations in POLQ and REV3L in POLE mutant tumors should undergo further investigation to determine whether POLQ and REV3L mutations contribute to the ultramutator phenotype and favorable outcome of patients with POLE mutant tumors.
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Affiliation(s)
- Fangjin Huang
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Hisashi Tanaka
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
- Samuel Oschin Cancer Research Institute (SOCCI), Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
- Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Beatrice S Knudsen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
- Samuel Oschin Cancer Research Institute (SOCCI), Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA.
| | - Joanne K Rutgers
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
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Nientiedt C, Endris V, Jenzer M, Mansour J, Sedehi NTP, Pecqueux C, Volckmar AL, Leichsenring J, Neumann O, Kirchner M, Hoveida S, Lantwin P, Kaltenecker K, Dieffenbacher S, Gasch C, Hofer L, Franke D, Tosev G, Görtz M, Schütz V, Radtke JP, Nyarangi-Dix J, Hatiboglu G, Simpfendörfer T, Schönberg G, Isaac S, Teber D, Koerber SA, Christofi G, Czink E, Kreuter R, Apostolidis L, Kratochwil C, Giesel F, Haberkorn U, Debus J, Sültmann H, Zschäbitz S, Jäger D, Duensing A, Schirmacher P, Grüllich C, Hohenfellner M, Stenzinger A, Duensing S. High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer -Results from a prospective pilot study using a 37 gene panel. Urol Oncol 2020; 38:637.e17-637.e27. [PMID: 32280037 DOI: 10.1016/j.urolonc.2020.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/14/2020] [Accepted: 03/02/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naïve patients with a high risk for lethal disease outcome, however, has not been sufficiently explored. PATIENTS AND METHODS Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel. RESULTS The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naïve metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naïve metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%). CONCLUSIONS This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naïve metastatic prostate cancer.
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Affiliation(s)
- Cathleen Nientiedt
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Maximilian Jenzer
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Josef Mansour
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Carine Pecqueux
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jonas Leichsenring
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Olaf Neumann
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Shirin Hoveida
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Philippa Lantwin
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Katrin Kaltenecker
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Claudia Gasch
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Luisa Hofer
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Desiree Franke
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Georgi Tosev
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Magdalena Görtz
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Viktoria Schütz
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan-Philipp Radtke
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Gencay Hatiboglu
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Gita Schönberg
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Sanjay Isaac
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dogu Teber
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan A Koerber
- Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
| | - Georgia Christofi
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Elena Czink
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Rebecca Kreuter
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Clemens Kratochwil
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frederik Giesel
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Uwe Haberkorn
- Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jürgen Debus
- Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
| | - Holger Sültmann
- Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Stefanie Zschäbitz
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Anette Duensing
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany; Cancer Therapeutics Program and Department of Pathology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, PA; Precision Oncology of Urological Malignancies, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Carsten Grüllich
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | | | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
| | - Stefan Duensing
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany; Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.
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Engel C, Ahadova A, Seppälä TT, Aretz S, Bigirwamungu-Bargeman M, Bläker H, Bucksch K, Büttner R, de Vos Tot Nederveen Cappel WT, Endris V, Holinski-Feder E, Holzapfel S, Hüneburg R, Jacobs MAJM, Koornstra JJ, Langers AM, Lepistö A, Morak M, Möslein G, Peltomäki P, Pylvänäinen K, Rahner N, Renkonen-Sinisalo L, Schulmann K, Steinke-Lange V, Stenzinger A, Strassburg CP, van de Meeberg PC, van Kouwen M, van Leerdam M, Vangala DB, Vecht J, Verhulst ML, von Knebel Doeberitz M, Weitz J, Zachariae S, Loeffler M, Mecklin JP, Kloor M, Vasen HF. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology 2020; 158:1326-1333. [PMID: 31926173 DOI: 10.1053/j.gastro.2019.12.032] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 12/05/2019] [Accepted: 12/24/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
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Affiliation(s)
- Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
| | - Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Toni T Seppälä
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; University of Helsinki, Helsinki, Finland; Johns Hopkins University, Surgical Oncology, Baltimore, Maryland
| | - Stefan Aretz
- Institute of Human Genetics, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | | | - Hendrik Bläker
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Karolin Bucksch
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | | | | | - Volker Endris
- Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Elke Holinski-Feder
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Center of Medical Genetics, Munich, Germany
| | - Stefanie Holzapfel
- Institute of Human Genetics, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Robert Hüneburg
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Maarten A J M Jacobs
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Jan J Koornstra
- Department of Gastroenterology & Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra M Langers
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Anna Lepistö
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland
| | - Monika Morak
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Center of Medical Genetics, Munich, Germany
| | - Gabriela Möslein
- Center for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke, Wuppertal, Germany
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Kirsi Pylvänäinen
- Department of Education and Science, Central Finland Hospital District, Jyväskylä, Finland
| | - Nils Rahner
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Laura Renkonen-Sinisalo
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland
| | - Karsten Schulmann
- Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany; MVZ Arnsberg, Medical Practice for Hematology and Oncology, Arnsberg, Germany
| | - Verena Steinke-Lange
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Center of Medical Genetics, Munich, Germany
| | - Albrecht Stenzinger
- Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian P Strassburg
- National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Paul C van de Meeberg
- Department of Gastroenterology & Hepatology, Slingeland Hospital, Doetinchem, The Netherlands
| | - Mariette van Kouwen
- Department of Gastroenterology & Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Monique van Leerdam
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Deepak B Vangala
- Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Juda Vecht
- Department of Gastroenterology & Hepatology, Isala Zwolle, Zwolle, The Netherlands
| | - Marie-Louise Verhulst
- Department of Gastroenterology & Hepatology, Maxima Medical Centre, Eindhoven, The Netherlands
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus of the Technical University Dresden, Dresden, Germany
| | - Silke Zachariae
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Markus Loeffler
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hans F Vasen
- Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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8
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[Morphomolecular characterization of colorectal neoplasms]. DER PATHOLOGE 2019; 40:265-270. [PMID: 31705232 DOI: 10.1007/s00292-019-00694-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Besides the classical histopathological examination, molecular characterization approaches are moving more and more into the center of clinical pathology. The association of tumors with distinct morphological features with specific molecular alterations can either help to underline a certain histologic diagnosis or to identify alterations that may serve as potential molecular targets. OBJECTIVES The aim of the presented studies was the morphomolecular characterization of colorectal neoplasias with either a distinct morphology or in specific clinical settings. MATERIALS AND METHODS Targeted massive parallel sequencing (MPS) of various colorectal neoplasias was performed in all of the presented studies. RESULTS Our studies showed the clinical utility of MPS for routine molecular diagnostics of colorectal carcinoma (CRC) in different clinical settings. In addition, we were able to demonstrate a close genetic relationship of colorectal adenoneuroendocrine carcinomas with classical CRC as well as a distinct genetic profile for appendiceal goblet cell neoplasias. CONCLUSIONS Morphomolecular characterization approaches not only enable the identification of potentially therapeutically relevant alterations, but also allow for the specific identification of morphologically distinct subtypes of colorectal neoplasias, which may be of diagnostic usefulness.
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9
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Kratochwil C, Giesel FL, Heussel CP, Kazdal D, Endris V, Nientiedt C, Bruchertseifer F, Kippenberger M, Rathke H, Leichsenring J, Hohenfellner M, Morgenstern A, Haberkorn U, Duensing S, Stenzinger A. Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair-Associated Genes. J Nucl Med 2019; 61:683-688. [PMID: 31601699 DOI: 10.2967/jnumed.119.234559] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/20/2019] [Indexed: 12/12/2022] Open
Abstract
Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT-nonresponding lesions by targeted next-generation sequencing. Methods: Of 60 patients treated with 225Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. Results: In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n = 3), CHEK2 (n = 2), ATM (n = 2), and BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB, and PMS1 (n = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC, and various FANC genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair-targeting agents such as poly(ADP-ribose)-polymerase inhibitors.
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Affiliation(s)
- Clemens Kratochwil
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Frederik L Giesel
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Claus-Peter Heussel
- Thorax Centre, Department of Interventional and Diagnostic Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Cathleen Nientiedt
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany.,Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany
| | - Frank Bruchertseifer
- Directorate for Nuclear Safety and Security, European Commission-Joint Research Centre, Karlsruhe, Germany
| | - Maximilian Kippenberger
- Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Rathke
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Jonas Leichsenring
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Markus Hohenfellner
- Department of Urology, Heidelberg University Hospital, Heidelberg, Germany; and
| | - Alfred Morgenstern
- Directorate for Nuclear Safety and Security, European Commission-Joint Research Centre, Karlsruhe, Germany
| | - Uwe Haberkorn
- Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.,Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany
| | - Stefan Duensing
- Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany.,Department of Urology, Heidelberg University Hospital, Heidelberg, Germany; and
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10
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Jenzer M, Keß P, Nientiedt C, Endris V, Kippenberger M, Leichsenring J, Stögbauer F, Haimes J, Mishkin S, Kudlow B, Kaczorowski A, Zschäbitz S, Volckmar AL, Sültmann H, Jäger D, Duensing A, Schirmacher P, Hohenfellner M, Grüllich C, Stenzinger A, Duensing S. The BRCA2 mutation status shapes the immune phenotype of prostate cancer. Cancer Immunol Immunother 2019; 68:1621-1633. [PMID: 31549213 PMCID: PMC6805809 DOI: 10.1007/s00262-019-02393-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 09/05/2019] [Indexed: 12/11/2022]
Abstract
Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.
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Affiliation(s)
- Maximilian Jenzer
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany.,Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Peter Keß
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Cathleen Nientiedt
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany.,Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Maximilian Kippenberger
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Jonas Leichsenring
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Fabian Stögbauer
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Josh Haimes
- ArcherDX, 2477 55th Street, Boulder, CO, 80301, USA
| | | | - Brian Kudlow
- ArcherDX, 2477 55th Street, Boulder, CO, 80301, USA
| | - Adam Kaczorowski
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Stefanie Zschäbitz
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany.,Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Holger Sültmann
- National Center for Tumor Diseases, German Cancer Research Center, Cancer Genome Research, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Anette Duensing
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, USA.,Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.,Section of Precision Oncology of Urological Malignancies, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany.,Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Markus Hohenfellner
- Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Carsten Grüllich
- Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.,Section of Translational Urooncology, Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
| | - Stefan Duensing
- Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany. .,Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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11
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Leichsenring J, Kazdal D, Ploeger C, Allgäuer M, Endris V, Volckmar AL, Neumann O, Kirchner M, Penzel R, Rempel E, Budczies J, Schirmacher P, Fröhling S, Stenzinger A. [From panel diagnostics to comprehensive genomic analysis : Infobesity or empowerment?]. DER PATHOLOGE 2019; 40:235-242. [PMID: 31089797 DOI: 10.1007/s00292-019-0608-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Precision oncology is obtaining a central role in the therapy of malignant diseases. The indication for targeted therapy is based on the identification of molecular targets for which next-generation sequencing (NGS) is commonly used nowadays. All approved predictive biomarkers and molecular targets, including gene fusions and copy number alterations, can be identified depending on panel design and method applied. Some clinical scenarios, however, may require more holistic genomic approaches, such as whole-genome/whole-exome and transcriptome analysis, which must be embedded in a clinical trial. Here, key aspects and applications of each method are summarized and discussed.
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Affiliation(s)
- J Leichsenring
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - D Kazdal
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Ploeger
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - M Allgäuer
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - V Endris
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - A-L Volckmar
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - O Neumann
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - M Kirchner
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - R Penzel
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - E Rempel
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - J Budczies
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - P Schirmacher
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - S Fröhling
- Abteilung Translationale Medizinische Onkologie, Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg und Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland
| | - A Stenzinger
- Pathologisches Institut, Molekularpathologisches Zentrum, Universitätsklinikum Heidelberg, Heidelberg, Deutschland.
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12
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Isnaldi E, Garuti A, Cirmena G, Scabini S, Rimini E, Ferrando L, Lia M, Murialdo R, Tixi L, Carminati E, Panaro A, Gallo M, Grillo F, Mastracci L, Repetto L, Fiocca R, Romairone E, Zoppoli G, Ballestrero A. Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer. J Transl Med 2019; 17:137. [PMID: 31036005 PMCID: PMC6489172 DOI: 10.1186/s12967-019-1879-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 04/09/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously. METHODS We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis. RESULTS We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status. CONCLUSIONS To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.
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Affiliation(s)
- Edoardo Isnaldi
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Anna Garuti
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Gabriella Cirmena
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Stefano Scabini
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Edoardo Rimini
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Lorenzo Ferrando
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Michela Lia
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Roberto Murialdo
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Lucia Tixi
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Enrico Carminati
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Andrea Panaro
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Maurizio Gallo
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Federica Grillo
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Luca Mastracci
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Lazzaro Repetto
- Department of Oncology, Ospedale Civile “G Borea”, Sanremo, Italy
| | - Roberto Fiocca
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Emanuele Romairone
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Gabriele Zoppoli
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
| | - Alberto Ballestrero
- Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Ospedale Policlinico San Martino IRCCS Per l’Oncologia, Genoa, Italy
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13
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Abstract
CLINICAL ISSUE Innovative next generation sequencing (NGS) technologies and comprehensive sequencing investigations in large patient cohorts have paved the way for very promising personalized treatment strategies based on the molecular characteristics of individual tumors. STANDARD TREATMENT Targeted therapies, such as tyrosine kinase inhibitors, antibodies and modern immunotherapeutic approaches are well established as monotherapy and combination therapy for many hematological and oncological malignancies. TREATMENT INNOVATIONS A plethora of innovative therapies targeting various components of intracellular signaling cascades and effective mechanisms against oncogenes as well as the availability of NGS technologies enable personalized cancer treatment based on the molecular profiles of individual tumors and genetic stratification, within clinical trials. DIAGNOSTIC WORK-UP Comprehensive genetic approaches including cancer gene panel sequencing, whole exome, whole genome and transcriptome sequencing are carried out to a varying extent and particularly in the academic setting. PERFORMANCE Principally, a comprehensive characterization of tumors in addition to DNA and RNA sequencing that also incorporates epigenetic, metabolomic, and proteomic alterations would be desirable. A comprehensive clinical implementation of integrative, multidimensional genetic typing is, however, currently not possible. ACHIEVEMENTS It remains to be demonstrated whether these approaches will translate into significantly better outcomes for patients and whether they can be increasingly implemented in the routine diagnostic work-up. PRACTICAL RECOMMENDATIONS The selection of diagnostic tools in individual cases and the extent of genomic analyses in the clinical context, need to take the availability of methods as well as the present clinical situation into account.
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Affiliation(s)
- C Heining
- Abteilung für Translationale Onkologie, Nationales Centrum für Tumorerkrankungen Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland
| | - P Horak
- Abteilung für Translationale Onkologie, Nationales Centrum für Tumorerkrankungen Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland
| | - S Gröschel
- Abteilung für Translationale Onkologie, Nationales Centrum für Tumorerkrankungen Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland
| | - H Glimm
- Abteilung für Translationale Onkologie, Nationales Centrum für Tumorerkrankungen Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland
| | - S Fröhling
- Abteilung für Translationale Onkologie, Nationales Centrum für Tumorerkrankungen Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland.
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14
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Radpour R, Forouharkhou F. Single-cell analysis of tumors: Creating new value for molecular biomarker discovery of cancer stem cells and tumor-infiltrating immune cells. World J Stem Cells 2018; 10:160-171. [PMID: 30631391 PMCID: PMC6325074 DOI: 10.4252/wjsc.v10.i11.160] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/18/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Biomarker-driven individualized treatment in oncology has made tremendous progress through technological developments, new therapeutic modalities and a deeper understanding of the molecular biology for tumors, cancer stem cells and tumor-infiltrating immune cells. Recent technical developments have led to the establishment of a variety of cancer-related diagnostic, prognostic and predictive biomarkers. In this regard, different modern OMICs approaches were assessed in order to categorize and classify prognostically different forms of neoplasia. Despite those technical advancements, the extent of molecular heterogeneity at the individual cell level in human tumors remains largely uncharacterized. Each tumor consists of a mixture of heterogeneous cell types. Therefore, it is important to quantify the dynamic cellular variations in order to predict clinical parameters, such as a response to treatment and or potential for disease recurrence. Recently, single-cell based methods have been developed to characterize the heterogeneity in seemingly homogenous cancer cell populations prior to and during treatment. In this review, we highlight the recent advances for single-cell analysis and discuss the challenges and prospects for molecular characterization of cancer cells, cancer stem cells and tumor-infiltrating immune cells.
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Affiliation(s)
- Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Farzad Forouharkhou
- Department for Bioinformatics, Persian Bioinformatics System, Tehran 14166, Iran
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15
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Lier A, Penzel R, Heining C, Horak P, Fröhlich M, Uhrig S, Budczies J, Kirchner M, Volckmar AL, Hutter B, Kreutzfeldt S, Endris V, Richter D, Wolf S, Pfütze K, Neumann O, Buchhalter I, Morais de Oliveira CM, Singer S, Leichsenring J, Herpel E, Klauschen F, Jost PJ, Metzeler KH, Schulze-Osthoff K, Kopp HG, Kindler T, Rieke DT, Lamping M, Brandts C, Falkenhorst J, Bauer S, Schröck E, Folprecht G, Boerries M, von Bubnoff N, Weichert W, Brors B, Lichter P, von Kalle C, Schirmacher P, Glimm H, Fröhling S, Stenzinger A. Validating Comprehensive Next-Generation Sequencing Results for Precision Oncology: The NCT/DKTK Molecularly Aided Stratification for Tumor Eradication Research Experience. JCO Precis Oncol 2018; 2:1-13. [DOI: 10.1200/po.18.00171] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Purpose Rapidly evolving genomics technologies, in particular comprehensive next-generation sequencing (NGS), have led to exponential growth in the understanding of cancer biology, shifting oncology toward personalized treatment strategies. However, comprehensive NGS approaches, such as whole-exome sequencing, have limitations that are related to the technology itself as well as to the input source. Hence, clinical implementation of comprehensive NGS in a quality-controlled diagnostic workflow requires both the standardization of sequencing procedures and continuous validation of sequencing results by orthogonal methods in an ongoing program to enable the determination of key test parameters and continuous improvement of NGS and bioinformatics pipelines. Patients and Methods We present validation data on 220 patients who were enrolled between 2013 and 2016 in a multi-institutional, genomics-guided precision oncology program (Molecularly Aided Stratification for Tumor Eradication Research) of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Results More than 90% of clinically actionable genomic alterations identified by combined whole-exome sequencing and transcriptome sequencing were successfully validated, with varying frequencies of discordant results across different types of alterations (fusions, 3.7%; single-nucleotide variants, 2.6%; amplifications, 1.1%; overexpression, 0.9%; deletions, 0.6%). The implementation of new computational methods for NGS data analysis led to a substantial improvement of gene fusion calling over time. Conclusion Collectively, these data demonstrate the value of a rigorous validation program that partners with comprehensive NGS to successfully implement and continuously improve cancer precision medicine in a clinical setting.
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Affiliation(s)
- Amelie Lier
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Roland Penzel
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Christoph Heining
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Peter Horak
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Martina Fröhlich
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Sebastian Uhrig
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Jan Budczies
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Martina Kirchner
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Anna-Lena Volckmar
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Barbara Hutter
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Simon Kreutzfeldt
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Volker Endris
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Daniela Richter
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Stephan Wolf
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Katrin Pfütze
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Olaf Neumann
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Ivo Buchhalter
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Cristiano M. Morais de Oliveira
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Stephan Singer
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Jonas Leichsenring
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Esther Herpel
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Frederick Klauschen
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Philipp J. Jost
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Klaus H. Metzeler
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Klaus Schulze-Osthoff
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Hans-Georg Kopp
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Thomas Kindler
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Damian T. Rieke
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Mario Lamping
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Christian Brandts
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Johanna Falkenhorst
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Sebastian Bauer
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Evelin Schröck
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Gunnar Folprecht
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Melanie Boerries
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Nikolas von Bubnoff
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Wilko Weichert
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Benedikt Brors
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Peter Lichter
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Christof von Kalle
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Peter Schirmacher
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Hanno Glimm
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Stefan Fröhling
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
| | - Albrecht Stenzinger
- Amelie Lier, Roland Penzel, Peter Horak, Jan Budczies, Martina Kirchner, Anna-Lena Volckmar, Simon Kreutzfeldt, Volker Endris, Olaf Neumann, Ivo Buchhalter, Cristiano M. Morais de Oliveira, Stephan Singer, Jonas Leichsenring, Esther Herpel, Christof von Kalle, Peter Schirmacher, Stefan Fröhling, and Albrecht Stenzinger, Heidelberg University Hospital; Christoph Heining, Daniela Richter, Stephan Wolf, Katrin Pfütze, Benedikt Brors, Peter Lichter, and Hanno Glimm, German Cancer Research Center; Peter Horak
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Volckmar AL, Endris V, Gaida MM, Leichsenring J, Stögbauer F, Allgäuer M, von Winterfeld M, Penzel R, Kirchner M, Brandt R, Neumann O, Sültmann H, Schirmacher P, Rudi J, Schmitz D, Stenzinger A. Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study. Genes Chromosomes Cancer 2018; 58:3-11. [PMID: 30230086 DOI: 10.1002/gcc.22682] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 09/07/2018] [Accepted: 09/10/2018] [Indexed: 12/15/2022] Open
Abstract
Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty-two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow-up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.
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Affiliation(s)
- Anna-Lena Volckmar
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jonas Leichsenring
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Fabian Stögbauer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael Allgäuer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Roland Penzel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Regine Brandt
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Olaf Neumann
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Holger Sültmann
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jochen Rudi
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus und St. Hedwigsklinik, Academic Teaching Hospital, Mannheim, Germany
| | - Daniel Schmitz
- Department of Gastroenterology, Oncology and Diabetology, Theresienkrankenhaus und St. Hedwigsklinik, Academic Teaching Hospital, Mannheim, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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17
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Jesinghaus M, Konukiewitz B, Foersch S, Stenzinger A, Steiger K, Muckenhuber A, Groß C, Mollenhauer M, Roth W, Detlefsen S, Weichert W, Klöppel G, Pfarr N, Schlitter AM. Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix. Mod Pathol 2018; 31:829-839. [PMID: 29327707 DOI: 10.1038/modpathol.2017.184] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 10/24/2017] [Accepted: 11/08/2017] [Indexed: 12/23/2022]
Abstract
The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling-associated genes (USP9X, NOTCH1, CTNNA1, CTNNB1, TRRAP). These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR directed therapy regimens.
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Affiliation(s)
- Moritz Jesinghaus
- Institute of Pathology, Technical University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Björn Konukiewitz
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | | | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Alexander Muckenhuber
- Institute of Pathology, Technical University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Claudia Groß
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | | | - Wilfried Roth
- Institute of Pathology, University Hospital Mainz, Mainz, Germany
| | - Sönke Detlefsen
- Department of Clinical Pathology, University Hospital Odense, Odense, Denmark
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Anna Melissa Schlitter
- Institute of Pathology, Technical University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
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18
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D'Haene N, Fontanges Q, De Nève N, Blanchard O, Melendez B, Delos M, Dehou MF, Maris C, Nagy N, Rousseau E, Vandenhove J, Gilles A, De Prez C, Verset L, Van Craynest MP, Demetter P, Van Laethem JL, Salmon I, Le Mercier M. Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience. Oncotarget 2018; 9:20761-20768. [PMID: 29755687 PMCID: PMC5945518 DOI: 10.18632/oncotarget.25099] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/17/2018] [Indexed: 01/14/2023] Open
Abstract
International guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-EGFR agents for metastatic colorectal cancer (CRC) patients. Daily, new data emerges on the theranostic and prognostic role of molecular biomarkers; this is a strong incentive for a validated, sensitive, and broadly available molecular screening test. Next-generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. We report here our 2 years of clinical practice using NGS results to guide therapeutic decisions. The Ion Torrent AmpliSeq colon/lung cancer panel, which allows mutation detection in 22 cancer-related genes, was prospectively used in clinical practice (BELAC ISO 15189 accredited method). The DNA of 741 formalin-fixed paraffin-embedded CRC tissues, including primary tumors and metastasis, was obtained from 14 different Belgian institutions and subjected to targeted NGS. Of the tumors tested, 98% (727) were successfully sequenced and 89% (650) harbored at least one mutation. KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively. These mutation frequencies were consistent with those reported in public databases. Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%). The median turnaround time between reception of the sample in the laboratory and report release was 8 calendar days. Overall, the AmpliSeq colon/lung cancer panel was successfully applied in daily practice and provided reliable clinically relevant information for CRC patients.
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Affiliation(s)
- Nicky D'Haene
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Quitterie Fontanges
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Nancy De Nève
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Oriane Blanchard
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Barbara Melendez
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Monique Delos
- Department of Pathology, CHU UCL Namur, Yvoir, Belgium
| | | | - Calliope Maris
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.,Department of Pathology, Braine l´Alleud Waterloo Hospital, Braine l´Alleud, Belgium
| | - Nathalie Nagy
- Department of Pathology, Charleroi University Hospital, Charleroi, Belgium
| | | | | | - André Gilles
- Department of Pathology, EPICURA Hospital, Frameries, Belgium
| | - Carine De Prez
- Department of Pathology, Brugmann University Hospital, Brussels, Belgium
| | - Laurine Verset
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.,CurePath, Jumet, Belgium
| | | | - Pieter Demetter
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Luc Van Laethem
- Department of Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Isabelle Salmon
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Marie Le Mercier
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
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19
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Kather JN, Halama N, Jaeger D. Genomics and emerging biomarkers for immunotherapy of colorectal cancer. Semin Cancer Biol 2018; 52:189-197. [PMID: 29501787 DOI: 10.1016/j.semcancer.2018.02.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/19/2018] [Accepted: 02/28/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.
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Affiliation(s)
- Jakob Nikolas Kather
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Niels Halama
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Dirk Jaeger
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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20
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Ahadova A, Gallon R, Gebert J, Ballhausen A, Endris V, Kirchner M, Stenzinger A, Burn J, von Knebel Doeberitz M, Bläker H, Kloor M. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer 2018; 143:139-150. [DOI: 10.1002/ijc.31300] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/26/2018] [Accepted: 02/01/2018] [Indexed: 12/25/2022]
Affiliation(s)
- Aysel Ahadova
- Department of Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; 69120 Heidelberg Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280; 69120 Heidelberg Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg; Heidelberg Germany
| | - Richard Gallon
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway; Newcastle upon Tyne United Kingdom
| | - Johannes Gebert
- Department of Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; 69120 Heidelberg Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280; 69120 Heidelberg Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg; Heidelberg Germany
| | - Alexej Ballhausen
- Department of Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; 69120 Heidelberg Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280; 69120 Heidelberg Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg; Heidelberg Germany
| | - Volker Endris
- Department of General Pathology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; Heidelberg 69120 Germany
| | - Martina Kirchner
- Department of General Pathology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; Heidelberg 69120 Germany
| | - Albrecht Stenzinger
- Department of General Pathology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; Heidelberg 69120 Germany
| | - John Burn
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway; Newcastle upon Tyne United Kingdom
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; 69120 Heidelberg Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280; 69120 Heidelberg Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg; Heidelberg Germany
| | - Hendrik Bläker
- Department of General Pathology; University Hospital Charité, Charitéplatz 1; Berlin 10117 Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224; 69120 Heidelberg Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280; 69120 Heidelberg Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg; Heidelberg Germany
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21
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Leichsenring J, Volckmar AL, Kirchner M, Kazdal D, Kriegsmann M, Stögbauer F, Bockmayr T, Klauschen F, Herth FJF, Penzel R, Warth A, Schirmacher P, Endris V, Stenzinger A. Targeted deep sequencing of effusion cytology samples is feasible, informs spatiotemporal tumor evolution, and has clinical and diagnostic utility. Genes Chromosomes Cancer 2017; 57:70-79. [PMID: 29044880 DOI: 10.1002/gcc.22509] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 10/05/2017] [Accepted: 10/11/2017] [Indexed: 12/12/2022] Open
Abstract
During the course of disease, many cancer patients eventually present with metastatic disease including peritoneal or pleural spread. In this context, cytology specimens derived from ascites or pleural effusion may help to differentiate malignant from benign conditions and sometimes yield diagnosis of a malignancy. However, even when supported by immunohistochemistry, cytological interpretation can be challenging, especially if tumor cellularity is low. Here, we investigated whether targeted deep sequencing of formalin-fixed and paraffin embedded (FFPE) cytology specimens of cancer patients is feasible, and has diagnostic and clinical impact. To this end, a cohort of 20 matched pairs was compiled, each comprising a cytology sample (FFPE cell block) and at least one biopsy/surgical resection specimen serving as benchmark. In addition, 5 non-malignant effusions were sequenced serving as negative-controls. All samples yielded sufficient libraries and were successfully subjected to targeted sequencing employing a semiconductor based next-generation sequencing platform. Using gene panels of different size and composition, including the Oncomine Comprehensive Assay, for targeted sequencing, somatic mutations were detected in the tissue of all 20 cases. Of these, 15 (75%) harbored mutations that were also detected in the corresponding cytology samples. In four of these cases (20%), additional private mutations were detected in either cytology or tissue samples, reflecting spatiotemporal tumor evolution. Of the five remaining cases, three (15%) showed wild type alleles in cytology material whereas tumor tissue had mutations in interrogated genes. Two cases were discordant, showing different private mutations in the cytology and in the tissue sample, respectively. In summary, sequencing of cytology specimens (FFPE cell block) reflecting spatiotemporal tumor evolution is feasible and yields adjunct genetic information that may be exploitable for diagnostics and therapy.
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Affiliation(s)
- Jonas Leichsenring
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Mark Kriegsmann
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Fabian Stögbauer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Teresa Bockmayr
- Institute of Pathology, Charité University Hospital, Berlin, Germany
| | | | - Felix J F Herth
- Department of Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.,Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
| | - Roland Penzel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Arne Warth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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22
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Abstract
Mutations in BRCA1 or BRCA2 define a subset of prostate cancer patients. Herein, we address the question whether BRCA1/2 mutations have a predictive impact on chemotherapy with docetaxel, a widely used drug in patients with metastatic castration resistant prostate cancer (mCRPC). Fifty-three men treated with docetaxel for mCRPC were tested for somatic BRCA1/2 mutations of the primary tumor. In a subgroup of patients, BRCA1/2 protein expression was tested as a potential surrogate marker for BRCA1/2 inactivation. Eight of 53 patients (15.1%) harbored a deleterious BRCA2 mutation. No BRCA1 mutation was found. Patients with a BRCA2 mutation showed a response rate of 25% to docetaxel in comparison to 71.1% in men with wildtype BRCA2 (p = 0.019). While the time to develop castration resistance was similar in both subgroups, the overall survival was significantly shorter in patients harboring a BRCA2 mutation. No correlation between the BRCA1/2 protein expression and the response to docetaxel was found. While the presence of a BRCA2 mutation does not preclude a response to docetaxel, there is overall a significant correlation between BRCA2 inactivation and a poor response rate. Our results suggest that a close oncological monitoring of patients with BRCA2 mutations for taxane resistance is warranted.
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23
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Horak P, Klink B, Heining C, Gröschel S, Hutter B, Fröhlich M, Uhrig S, Hübschmann D, Schlesner M, Eils R, Richter D, Pfütze K, Geörg C, Meißburger B, Wolf S, Schulz A, Penzel R, Herpel E, Kirchner M, Lier A, Endris V, Singer S, Schirmacher P, Weichert W, Stenzinger A, Schlenk RF, Schröck E, Brors B, von Kalle C, Glimm H, Fröhling S. Precision oncology based on omics data: The NCT Heidelberg experience. Int J Cancer 2017; 141:877-886. [PMID: 28597939 DOI: 10.1002/ijc.30828] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/24/2017] [Accepted: 05/29/2017] [Indexed: 12/17/2022]
Abstract
Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high-resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next-generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole-exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence-based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case-by-case basis toward controlled clinical trials of genomics-guided treatments.
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Affiliation(s)
- Peter Horak
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Barbara Klink
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Christoph Heining
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Gröschel
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,Research Group Molecular Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.,DKTK, Heidelberg, Germany
| | - Barbara Hutter
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Martina Fröhlich
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Sebastian Uhrig
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Daniel Hübschmann
- Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.,Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Roland Eils
- Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.,Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg, Germany
| | - Daniela Richter
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katrin Pfütze
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany
| | - Christina Geörg
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany
| | - Bettina Meißburger
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany
| | - Stephan Wolf
- Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Angela Schulz
- Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Roland Penzel
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Esther Herpel
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Amelie Lier
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stephan Singer
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Schirmacher
- DKTK, Heidelberg, Germany.,Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technische Universität München, Munich, Germany.,DKTK, Munich, Germany
| | - Albrecht Stenzinger
- DKTK, Heidelberg, Germany.,Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Evelin Schröck
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Benedikt Brors
- DKTK, Heidelberg, Germany.,Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Christof von Kalle
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,DKTK, Heidelberg, Germany.,DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany
| | - Hanno Glimm
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,DKTK, Heidelberg, Germany
| | - Stefan Fröhling
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,DKTK, Heidelberg, Germany
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24
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Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy. DNA Repair (Amst) 2017; 56:16-25. [PMID: 28687338 DOI: 10.1016/j.dnarep.2017.06.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.
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25
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Budczies J, Bockmayr M, Klauschen F, Endris V, Fröhling S, Schirmacher P, Denkert C, Stenzinger A. Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan-cancer survey with implications for the use of immune checkpoint inhibitors. Genes Chromosomes Cancer 2017; 56:651-659. [PMID: 28466543 DOI: 10.1002/gcc.22468] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/18/2017] [Accepted: 04/25/2017] [Indexed: 01/01/2023] Open
Abstract
Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated. Very recent work indicates that mutations in B2M, JAK1, and JAK2 render melanoma resistant to immune checkpoint blockade, thus serving as negative response predictors. Using the TCGA dataset, we performed a pan-cancer analysis of potentially damaging mutations in key genes implicated in antigen presentation and interferon-gamma signaling and investigated associations with transcript levels of immune checkpoint genes, cytolytic activity, and mutational burden. For B2M, JAK1, and JAK2, we observed overall mutation frequencies of 1.8%, 2%, and 2.6%, respectively, and found significant associations with mutational burden. On pathway level, melanoma as well as bladder, gastric, and lung cancer were most frequently affected by putative resistance mutations with mutation rates of 27%-50% in the antigen presentation pathway and of 16%-21% in the interferon signaling pathway. Our analysis suggests that a significant number of tumors harbor mutations that may negatively interfere with immune checkpoint inhibition, or confer a higher likelihood of resistance for which a second hit is ultimately required. Since these mutations are prevalent in treatment-naïve tumors, genetic screening prior to therapy might complement current approaches at predicting response to immune checkpoint blockade.
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Affiliation(s)
- Jan Budczies
- Institute of Pathology, Charité University Hospital, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Bockmayr
- Institute of Pathology, Charité University Hospital, Berlin, Germany.,Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frederick Klauschen
- Institute of Pathology, Charité University Hospital, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Fröhling
- German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Schirmacher
- German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Carsten Denkert
- Institute of Pathology, Charité University Hospital, Berlin, Germany.,German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Albrecht Stenzinger
- German Cancer Consortium (DKTK), Partner Sites Berlin and Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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26
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Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol 2017; 30:610-619. [PMID: 28059096 DOI: 10.1038/modpathol.2016.220] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/07/2016] [Accepted: 11/08/2016] [Indexed: 02/07/2023]
Abstract
Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.
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27
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Teo MY, Bambury RM, Zabor EC, Jordan E, Al-Ahmadie H, Boyd ME, Bouvier N, Mullane SA, Cha EK, Roper N, Ostrovnaya I, Hyman DM, Bochner BH, Arcila ME, Solit DB, Berger MF, Bajorin DF, Bellmunt J, Iyer G, Rosenberg JE. DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma. Clin Cancer Res 2017; 23:3610-3618. [PMID: 28137924 DOI: 10.1158/1078-0432.ccr-16-2520] [Citation(s) in RCA: 219] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 01/05/2017] [Accepted: 01/24/2017] [Indexed: 12/21/2022]
Abstract
Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes.Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. Clin Cancer Res; 23(14); 3610-8. ©2017 AACR.
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Affiliation(s)
- Min Yuen Teo
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Richard M Bambury
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
| | - Emily C Zabor
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Emmet Jordan
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hikmat Al-Ahmadie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mariel E Boyd
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy Bouvier
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Eugene K Cha
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nitin Roper
- Medical Oncology Service, National Cancer Institute, Bethesda, Maryland
| | - Irina Ostrovnaya
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David M Hyman
- Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bernard H Bochner
- Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria E Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David B Solit
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael F Berger
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dean F Bajorin
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joaquim Bellmunt
- Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gopakumar Iyer
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jonathan E Rosenberg
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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28
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Deans ZC, Costa JL, Cree I, Dequeker E, Edsjö A, Henderson S, Hummel M, Ligtenberg MJ, Loddo M, Machado JC, Marchetti A, Marquis K, Mason J, Normanno N, Rouleau E, Schuuring E, Snelson KM, Thunnissen E, Tops B, Williams G, van Krieken H, Hall JA. Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL. Virchows Arch 2017; 470:5-20. [PMID: 27678269 PMCID: PMC5243883 DOI: 10.1007/s00428-016-2025-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 08/27/2016] [Accepted: 09/16/2016] [Indexed: 10/31/2022]
Abstract
The clinical demand for mutation detection within multiple genes from a single tumour sample requires molecular diagnostic laboratories to develop rapid, high-throughput, highly sensitive, accurate and parallel testing within tight budget constraints. To meet this demand, many laboratories employ next-generation sequencing (NGS) based on small amplicons. Building on existing publications and general guidance for the clinical use of NGS and learnings from germline testing, the following guidelines establish consensus standards for somatic diagnostic testing, specifically for identifying and reporting mutations in solid tumours. These guidelines cover the testing strategy, implementation of testing within clinical service, sample requirements, data analysis and reporting of results. In conjunction with appropriate staff training and international standards for laboratory testing, these consensus standards for the use of NGS in molecular pathology of solid tumours will assist laboratories in implementing NGS in clinical services.
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Affiliation(s)
- Zandra C Deans
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK.
| | - Jose Luis Costa
- i3S Instituto de Investigação e Inovação em Saúde/IPATIMUP Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Ian Cree
- Department of Pathology, University Hospital Coventry and Warwickshire, Coventry, CV2 2DX, UK
| | - Els Dequeker
- Biomedical Quality Assurance Research Unit, Department of Public Health and Primary Care, KU Leuven-University of Leuven, Leuven, Belgium
| | - Anders Edsjö
- Clinical Pathology, Laboratory Medicine, Medical Services, Region Skåne, Lund, Sweden
| | - Shirley Henderson
- Genomics England, Queen Mary University of London, Dawson Hall, Charterhouse Square, London, EC1M 6BQ, UK
| | - Michael Hummel
- Institute of Pathology, Berlin, Germany and the DGP, German Society of Pathology, Charite, University Medicine Berlin, Berlin, Germany
| | - Marjolijn Jl Ligtenberg
- Department of Pathology and Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marco Loddo
- Oncologica UK Ltd, Suite 15-16, The Science Village, Chesterford Research Park, Cambridge, CB10 1XL, UK
| | - Jose Carlos Machado
- i3S Instituto de Investigação e Inovação em Saúde/IPATIMUP Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Antonio Marchetti
- Center of Predictive Molecular Medicine, CeSI-MeT, University of Chieti, Chieti, Italy
| | - Katherine Marquis
- Oncologica UK Ltd, Suite 15-16, The Science Village, Chesterford Research Park, Cambridge, CB10 1XL, UK
| | - Joanne Mason
- Genomics England, Queen Mary University of London, Dawson Hall, Charterhouse Square, London, EC1M 6BQ, UK
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumouri "Fondazione Giovanni Pascale" IRCCS, Naples, Italy
| | - Etienne Rouleau
- Department of Medical Biology and Pathology, Genetic and Pathology Molecular Service, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France
| | - Ed Schuuring
- Department of Pathology, University of Groningen, University Medical Center of Groningen, Groningen, The Netherlands
| | - Keeda-Marie Snelson
- Oncologica UK Ltd, Suite 15-16, The Science Village, Chesterford Research Park, Cambridge, CB10 1XL, UK
| | - Erik Thunnissen
- Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Bastiaan Tops
- Department of Pathology and Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gareth Williams
- Oncologica UK Ltd, Suite 15-16, The Science Village, Chesterford Research Park, Cambridge, CB10 1XL, UK
| | - Han van Krieken
- Department of Pathology and Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jacqueline A Hall
- International Quality Network for Pathology (IQN Path) Association Sans But Lucratif (A.S.B.L), 17 Boulevard Royal, L2449, Luxembourg City, Luxembourg
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
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29
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Fontanges Q, De Mendonca R, Salmon I, Le Mercier M, D'Haene N. Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers. Int J Mol Sci 2016; 17:ijms17122117. [PMID: 27999270 PMCID: PMC5187917 DOI: 10.3390/ijms17122117] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/01/2016] [Accepted: 12/09/2016] [Indexed: 01/01/2023] Open
Abstract
Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials. Next generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. Targeted NGS is a method that allows parallel sequencing of thousands of short DNA sequences in a single test offering a cost-effective approach for detecting multiple genetic alterations with a minimum amount of DNA. In the present review, we collected data concerning the clinical application of NGS technology in the setting of colorectal cancer.
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Affiliation(s)
- Quitterie Fontanges
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
| | - Ricardo De Mendonca
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
| | - Isabelle Salmon
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
| | - Marie Le Mercier
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
| | - Nicky D'Haene
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
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30
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Serratì S, De Summa S, Pilato B, Petriella D, Lacalamita R, Tommasi S, Pinto R. Next-generation sequencing: advances and applications in cancer diagnosis. Onco Targets Ther 2016; 9:7355-7365. [PMID: 27980425 PMCID: PMC5144906 DOI: 10.2147/ott.s99807] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Technological advances have led to the introduction of next-generation sequencing (NGS) platforms in cancer investigation. NGS allows massive parallel sequencing that affords maximal tumor genomic assessment. NGS approaches are different, and concern DNA and RNA analysis. DNA sequencing includes whole-genome, whole-exome, and targeted sequencing, which focuses on a selection of genes of interest for a specific disease. RNA sequencing facilitates the detection of alternative gene-spliced transcripts, posttranscriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, small and long noncoding RNAs, and changes in gene expression. Most applications are in the cancer research field, but lately NGS technology has been revolutionizing cancer molecular diagnostics, due to the many advantages it offers compared to traditional methods. There is greater knowledge on solid cancer diagnostics, and recent interest has been shown also in the field of hematologic cancer. In this review, we report the latest data on NGS diagnostic/predictive clinical applications in solid and hematologic cancers. Moreover, since the amount of NGS data produced is very large and their interpretation is very complex, we briefly discuss two bioinformatic aspects, variant-calling accuracy and copy-number variation detection, which are gaining a lot of importance in cancer-diagnostic assessment.
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Affiliation(s)
- Simona Serratì
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Simona De Summa
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Brunella Pilato
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Daniela Petriella
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Rosanna Lacalamita
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Stefania Tommasi
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Rosamaria Pinto
- Molecular Genetics Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
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31
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O'Hara MH, Hamilton SR, O'Dwyer PJ. Molecular Triage Trials in Colorectal Cancer. Cancer J 2016; 22:218-22. [PMID: 27341602 DOI: 10.1097/ppo.0000000000000199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Advances in the understanding of genomic alterations in cancer, and the various therapies targeted to these alterations have permitted the design of trials directed to bringing this science to the clinic, with the ultimate goal of tailoring therapy to the individual. There is a high need for advances in targeted therapy in colorectal cancer, a disease in which only 2 classes of targeted therapies are approved for use in colorectal cancer, despite the majority of colorectal cancers containing a potentially targetable mutation. Here we outline the key elements to the design of these clinical trials and summarize the current active molecular triage trials in colorectal cancer.
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Affiliation(s)
- Mark H O'Hara
- From the *Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; and †The University of Texas MD Anderson Cancer Center, Houston, TX
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