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Wang J, Guo C, Wang J, Zhang X, Qi J, Huang X, Hu Z, Wang H, Hong B. Tumor Mutation Signature Reveals the Risk Factors of Lung Adenocarcinoma with EGFR or KRAS Mutation. Cancer Control 2025; 32:10732748241307363. [PMID: 39760242 DOI: 10.1177/10732748241307363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025] Open
Abstract
INTRODUCTION EGFR and KRAS mutations are frequently detected in lung adenocarcinoma (LUAD). Tumor mutational signature (TMS) determination is an approach to identify somatic mutational patterns associated with pathogenic factors. In this study, through the analysis of TMS, the underlying pathogenic factors of LUAD with EGFR and KRAS mutations were traced. METHODS This was a retrospective study. TMS of LUAD with KRAS and EGFR mutations from the TCGA, OncoSG, and MSK datasets was determined by two bioinformatics tools, namely the "MutationalPatterns" and "FitMS" packages. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) of LUAD clinical specimens was analyzed using capillary electrophoresis. RESULTS In LUAD with KRAS mutations, TMS analysis indicated that the smoking-related SBS4 signature was enriched. For LUAD with EGFR L858R mutation, the smoking-related SBS4 signature was enriched in the Western population from the TCGA database; however, the smoking-related SBS4 signature was not obvious in Asian LUAD patients. LUAD with EGFR exon19 deletion (19Del) exhibited stronger SBS15 signature, which was related to defective DNA mismatch repair. Capillary electrophoresis analysis showed that an EMAST locus was frequently instable in LUAD with EGFR 19Del. Different from the Western population, Asian LUAD patients with EGFR mutations exhibited the enrichment of SBS1, SBS2, and SBS13 signatures, which were associated with the endogenous mutation process of cytidine deamination. CONCLUSIONS TMS analysis reveals that smoking is associated with LUAD with KRAS mutations. Defective DNA mismatch repair and endogenous cytidine deamination are associated with LUAD with EGFR mutations, especially for the EGFR 19Del. The endogenous mutational process is stronger in Asian LUAD patients than Western LUAD patients.
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Affiliation(s)
- Jialiang Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Chang Guo
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Jiexiao Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Xiaopeng Zhang
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Jian Qi
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Xiang Huang
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Zongtao Hu
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Hongzhi Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Bo Hong
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
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Fiegl A, Wendler O, Giedl J, Gaisa NT, Richter G, Campean V, Burger M, Simmer F, Nagtegaal I, Wullich B, Bertz S, Hartmann A, Stoehr R. Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) in Penile Squamous Cell Carcinoma-No Evidence for a Role in Carcinogenesis. Curr Oncol 2024; 31:5752-5761. [PMID: 39451731 PMCID: PMC11505989 DOI: 10.3390/curroncol31100427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/16/2024] [Accepted: 09/19/2024] [Indexed: 10/26/2024] Open
Abstract
Penile squamous cell carcinoma (pSCC) is a rare malignancy with a global incidence ranging from 0.1 to 0.7 per 100,000 males. Prognosis is generally favorable for localized tumors, but metastatic pSCC remains challenging, with low survival rates. The role of novel biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), in predicting the response to immune checkpoint inhibitors (ICIs) has been investigated in various cancers. However, MSI has not been observed in pSCC, limiting immunotherapy options for this patient subgroup. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a distinct form of genomic instability associated with deficient MSH3 expression, which has been proposed as a potential biomarker in several cancers. This study investigates EMAST and MSH3 expression in a cohort of 78 pSCC cases using PCR, fragment analysis and immunohistochemistry. For the detection of EMAST, the stability of five microsatellite markers (D9S242, D20S82, MYCL1, D8S321 and D20S85) was analyzed. None of the cases showed an instability. As for MSH3 immunohistochemistry, all analyzable cases showed retained MSH3 expression. These results strongly suggest that neither EMAST nor MSH3 deficiency is involved in the carcinogenesis of pSCC and do not represent reliable predictive biomarkers in this entity. Furthermore, these findings are in full agreement with our previous study showing a very low frequency of MSI and further support the thesis that EMAST and MSI are strongly interconnected forms of genomic instability. Further research is needed to explore novel therapeutic targets and predictive biomarkers for immunotherapy in this patient population.
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Affiliation(s)
- August Fiegl
- Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.F.); (J.G.); (S.B.); (A.H.)
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Olaf Wendler
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
- Department of Otorhinolaryngology—Head and Neck Surgery, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Johannes Giedl
- Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.F.); (J.G.); (S.B.); (A.H.)
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Nadine T. Gaisa
- Institute of Pathology, University Hospital Ulm, 89081 Ulm, Germany
- Institute of Pathology, RWTH Aachen University, 52062 Aachen, Germany
| | | | | | - Maximilian Burger
- St. Josef Medical Centre, Department of Urology, University Regensburg, 93053 Regensburg, Germany;
| | - Femke Simmer
- Department of Pathology, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands;
| | - Iris Nagtegaal
- Department of Urology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany;
| | - Bernd Wullich
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
- Department of Urology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany;
| | - Simone Bertz
- Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.F.); (J.G.); (S.B.); (A.H.)
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.F.); (J.G.); (S.B.); (A.H.)
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
| | - Robert Stoehr
- Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.F.); (J.G.); (S.B.); (A.H.)
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany; (O.W.)
- Bavarian Cancer Research Center (BZKF), 91052 Erlangen, Germany
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Vuković Đerfi K, Salar A, Cacev T, Kapitanović S. EMAST Type of Microsatellite Instability-A Distinct Entity or Blurred Overlap between Stable and MSI Tumors. Genes (Basel) 2023; 14:1474. [PMID: 37510378 PMCID: PMC10380056 DOI: 10.3390/genes14071474] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.
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Affiliation(s)
- Kristina Vuković Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Anamarija Salar
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Tamara Cacev
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
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Malinaric R, Mantica G, Lo Monaco L, Mariano F, Leonardi R, Simonato A, Van der Merwe A, Terrone C. The Role of Novel Bladder Cancer Diagnostic and Surveillance Biomarkers-What Should a Urologist Really Know? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19159648. [PMID: 35955004 PMCID: PMC9368399 DOI: 10.3390/ijerph19159648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 07/29/2022] [Accepted: 07/31/2022] [Indexed: 05/20/2023]
Abstract
The aim of this review is to analyze and describe the current landscape of bladder cancer diagnostic and surveillance biomarkers. We researched the literature from 2016 to November 2021 to find the most promising new molecules and divided them into seven different subgroups based on their function and location in the cell. Although cystoscopy and cytology are still the gold standard for diagnosis and surveillance when it comes to bladder cancer (BCa), their cost is quite a burden for national health systems worldwide. Currently, the research is focused on finding a biomarker that has high negative predictive value (NPV) and can exclude with a certainty the presence of the tumor, considering missing it could be disastrous for the patient. Every subgroup has its own advantages and disadvantages; for example, protein biomarkers cost less than genomic ones, but on the other hand, they seem to be less precise. We tried to simplify this complicated topic as much as possible in order to make it comprehensible to doctors and urologists that are not as familiar with it, as well as encourage them to actively participate in ongoing research.
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Affiliation(s)
- Rafaela Malinaric
- Department of Urology, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy
- Correspondence:
| | - Guglielmo Mantica
- Department of Urology, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
| | - Lorenzo Lo Monaco
- Department of Urology, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy
| | - Federico Mariano
- Department of Urology, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy
| | - Rosario Leonardi
- Department of Urology, Casa di Cura Musumeci GECAS, 95030 Gravina di Catania, Italy
| | - Alchiede Simonato
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, 90133 Palermo, Italy
| | - André Van der Merwe
- Department of Urology, Tygerberg Academic Hospital, Stellenbosch University, Cape Town 7600, South Africa
| | - Carlo Terrone
- Department of Urology, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy
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5
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Song Y, Baxter SS, Dai L, Sanders C, Burkett S, Baugher RN, Mellott SD, Young TB, Lawhorn HE, Difilippantonio S, Karim B, Kadariya Y, Pinto LA, Testa JR, Shoemaker RH. Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability. Cancers (Basel) 2022; 14:3108. [PMID: 35804881 PMCID: PMC9264972 DOI: 10.3390/cancers14133108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/10/2022] [Accepted: 06/21/2022] [Indexed: 12/10/2022] Open
Abstract
Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/-;Nf2+/- mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting.
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Affiliation(s)
- Yurong Song
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (S.S.B.); (L.D.); (L.A.P.)
| | - Shaneen S. Baxter
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (S.S.B.); (L.D.); (L.A.P.)
| | - Lisheng Dai
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (S.S.B.); (L.D.); (L.A.P.)
| | - Chelsea Sanders
- Animal Research Technical Support of Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (C.S.); (S.D.)
| | - Sandra Burkett
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA;
| | - Ryan N. Baugher
- CLIA Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (R.N.B.); (S.D.M.); (T.B.Y.); (H.E.L.)
| | - Stephanie D. Mellott
- CLIA Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (R.N.B.); (S.D.M.); (T.B.Y.); (H.E.L.)
| | - Todd B. Young
- CLIA Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (R.N.B.); (S.D.M.); (T.B.Y.); (H.E.L.)
| | - Heidi E. Lawhorn
- CLIA Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (R.N.B.); (S.D.M.); (T.B.Y.); (H.E.L.)
| | - Simone Difilippantonio
- Animal Research Technical Support of Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (C.S.); (S.D.)
| | - Baktiar Karim
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;
| | - Yuwaraj Kadariya
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.K.); (J.R.T.)
| | - Ligia A. Pinto
- Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; (S.S.B.); (L.D.); (L.A.P.)
| | - Joseph R. Testa
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.K.); (J.R.T.)
| | - Robert H. Shoemaker
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA;
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Herz AL, Wisser S, Kohlruss M, Slotta-Huspenina J, Jesinghaus M, Grosser B, Steiger K, Novotny A, Hapfelmeier A, Schmidt T, Gaida MM, Weichert W, Keller G. Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact? JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2022; 8:233-244. [PMID: 35099128 PMCID: PMC8977279 DOI: 10.1002/cjp2.257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/21/2022]
Abstract
We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro‐oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein–Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI‐high (MSI‐H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI‐H and EBV‐negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4–63.6) compared with 38.7 months (95% CI 26.3–51.1) for the EMAST‐negative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2–75.2) and 38.7 months (95% CI 26.2–51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI‐H and EMAST and they indicate that EMAST alone is not a distinct instability type associated with noticeable clinico‐pathological characteristics of gastric carcinoma patients.
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Affiliation(s)
- Anna-Lina Herz
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Sarah Wisser
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Meike Kohlruss
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Slotta-Huspenina
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Moritz Jesinghaus
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Pathology, University Hospital Marburg, Marburg, Germany
| | - Bianca Grosser
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Pathology and Molecular Diagnostics, University Hospital Augsburg, Augsburg, Germany
| | - Katja Steiger
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.,German Cancer Consortium [DKTK], Partner Site Munich, Institute of Pathology, Munich, Germany
| | - Alexander Novotny
- Department of Surgery, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Alexander Hapfelmeier
- Institute for AI and Informatics in Medicine, Technical University of Munich, Munich, Germany.,Institute of General Practice and Health Services Research, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Thomas Schmidt
- Department of Surgery, University of Heidelberg, Heidelberg, Germany.,Department of Surgery, Universitätsklinikum Köln, Köln, Germany
| | - Matthias M Gaida
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany.,Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Wilko Weichert
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.,German Cancer Consortium [DKTK], Partner Site Munich, Institute of Pathology, Munich, Germany
| | - Gisela Keller
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
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7
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Kondelin J, Martin S, Katainen R, Renkonen-Sinisalo L, Lepistö A, Koskensalo S, Böhm J, Mecklin JP, Cajuso T, Hänninen UA, Välimäki N, Ravantti J, Rajamäki K, Palin K, Aaltonen LA. No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers. Genes Chromosomes Cancer 2021; 60:463-473. [PMID: 33527622 DOI: 10.1002/gcc.22941] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/20/2022] Open
Abstract
Microsatellite instability (MSI) is caused by defective DNA mismatch repair (MMR), and manifests as accumulation of small insertions and deletions (indels) in short tandem repeats of the genome. Another form of repeat instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), has been suggested to occur in 50% to 60% of colorectal cancer (CRC), of which approximately one quarter are accounted for by MSI. Unlike for MSI, the criteria for defining EMAST is not consensual. EMAST CRCs have been suggested to form a distinct subset of CRCs that has been linked to a higher tumor stage, chronic inflammation, and poor prognosis. EMAST CRCs not exhibiting MSI have been proposed to show instability of di- and trinucleotide repeats in addition to tetranucleotide repeats, but lack instability of mononucleotide repeats. However, previous studies on EMAST have been based on targeted analysis of small sets of marker repeats, often in relatively few samples. To gain insight into tetranucleotide instability on a genome-wide level, we utilized whole genome sequencing data from 227 microsatellite stable (MSS) CRCs, 18 MSI CRCs, 3 POLE-mutated CRCs, and their corresponding normal samples. As expected, we observed tetranucleotide instability in all MSI CRCs, accompanied by instability of mono-, di-, and trinucleotide repeats. Among MSS CRCs, some tumors displayed more microsatellite mutations than others as a continuum, and no distinct subset of tumors with the previously proposed molecular characters of EMAST could be observed. Our results suggest that tetranucleotide repeat mutations in non-MSI CRCs represent stochastic mutation events rather than define a distinct CRC subclass.
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Affiliation(s)
- Johanna Kondelin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Samantha Martin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Riku Katainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Laura Renkonen-Sinisalo
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland
| | - Anna Lepistö
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland
| | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Helsinki, Finland
| | - Jan Böhm
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, Jyväskylä Central Hospital, Jyväskylä, Finland.,Department Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Tatiana Cajuso
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Ulrika A Hänninen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Niko Välimäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Janne Ravantti
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Kristiina Rajamäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Kimmo Palin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
| | - Lauri A Aaltonen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
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8
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Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J. Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel) 2020; 12:E3319. [PMID: 33182707 PMCID: PMC7697596 DOI: 10.3390/cancers12113319] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/30/2020] [Accepted: 11/07/2020] [Indexed: 01/05/2023] Open
Abstract
Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for dMMR is now routine for endometrial cancer. Somatic mutations leading to dMMR account for approximately 90% of these cancers. However, in 5-10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies. So far, gynecological cancers with dMMR/MSI are not well characterized and markers for detection of MSI in gynecological cancers are not well defined. In addition, currently advanced endometrial cancers have a poor prognosis and are treated without regard to MSI status. Elucidation of the mechanism causing dMMR/MSI gynecological cancers would aid in diagnosis and therapeutic intervention. Recently, a new immunotherapy was approved for the treatment of solid tumors with MSI that have recurred or progressed after failing traditional treatment strategies. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers.
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Affiliation(s)
- Madhura Deshpande
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA; (M.D.); (P.A.R.); (Z.R.)
| | - Phillip A. Romanski
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA; (M.D.); (P.A.R.); (Z.R.)
| | - Zev Rosenwaks
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA; (M.D.); (P.A.R.); (Z.R.)
| | - Jeannine Gerhardt
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA; (M.D.); (P.A.R.); (Z.R.)
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
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9
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Raeker MO, Carethers JM. Immunological Features with DNA Microsatellite Alterations in Patients with Colorectal Cancer. JOURNAL OF CANCER IMMUNOLOGY 2020; 2:116-127. [PMID: 33000102 DOI: 10.33696/cancerimmunol.2.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Competent human DNA mismatch repair (MMR) corrects DNA polymerase mistakes made during cell replication to maintain complete DNA fidelity in daughter cells; faulty DNA MMR occurs in the setting of inflammation and neoplasia, creating base substitutions (e.g. point mutations) and frameshift mutations at DNA microsatellite sequences in progeny cells. Frameshift mutations at DNA microsatellite sequences are a detected biomarker termed microsatellite instability (MSI) for human disease, as this marker can prognosticate and determine therapeutic approaches for patients with cancer. There are two types of MSI: MSI-High (MSI-H), defined by frameshifts at mono- and di-nucleotide microsatellite sequences, and elevated microsatellite alterations at selected tetranucleotide repeats or EMAST, defined by frameshifts in di- and tetranucleotide microsatellite sequences but not mononucleotide sequences. Patients with colorectal cancers (CRCs) manifesting MSI-H demonstrate improved survival over patients without an MSI-H tumor, driven by the generation of immunogenic neoantigens caused by novel truncated proteins from genes whose sequences contain coding microsatellites; these patients' tumors contain hundreds of somatic mutations, and show responsiveness to treatment with immune checkpoint inhibitors. Patients with CRCs manifesting EMAST demonstrate poor survival over patients without an EMAST tumor, and may be driven by a more dominant defect in double strand break repair attributed to the MMR protein MSH3 over its frameshift correcting function; these patients' tumors often have a component of inflammation (and are also termed inflammation-associated microsatellite alterations) and show less somatic mutations and lack coding mononucleotide frameshift mutations that seem to generate the neoantigens seen in the majority of MSI-H tumors. Overall, both types of MSI are biomarkers that can prognosticate patients with CRC, can be tested for simultaneously in marker panels, and informs the approach to specific therapy including immunotherapy for their cancers.
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Affiliation(s)
- Maide O Raeker
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - John M Carethers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.,Department of Human Genetics and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
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10
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Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement. Clin Transl Gastroenterol 2020; 10:e00105. [PMID: 31789935 PMCID: PMC6970556 DOI: 10.14309/ctg.0000000000000105] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES: Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. METHODS: We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. RESULTS: UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). DISCUSSION: Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.
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11
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Garde-García H, Redondo-González E, Maestro-de Las Casas M, Fernández-Pérez C, Moreno-Sierra J. Biomarkers and intermediate-high risk non-muscle invasive bladder cancer: a multivariate analysis of three different cellular pathways with pronostic implications. Clin Transl Oncol 2020; 23:840-845. [PMID: 32839927 DOI: 10.1007/s12094-020-02476-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 08/06/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE To determine the presence of a group of mutations, and establish the prognostic value for recurrence and progression. MATERIALS AND METHODS Prospective observational study. Intermediate-to-high-risk non-muscle invasive bladder cancer (NMIBC) was evaluated. Data from genetic analyses were included in a database along with clinicopathological variables of interest. RESULTS Seventy-four patients. Twenty-five (33.8%) recurred and 3 (4.1%) progressed. Median time to recurrence: 8 months (5.7-12.7). Median time to progression: 14 months (P75: 12). Mutation distribution: KRAS codon 12: one patient (1.4%), BAT25: five patients (6.8%), BAT-26: four patients (5.4%), and D2S123: 6 patients (8.1%). Arg72Pro polymorphism: 50 patients (67.6%) exhibited homozygous mutations, 23 (31.1%) were heterozygous, and 1 patient (1.4%) did not present the mutation. We found an association between presence of MSI at BAT26 and female sex (p < 0.05) and tumor stage and the TP53 Arg72Pro polymorphism. Recurrence-free survival (RFS) was significantly associated with presence of MSI at D2S123, with a HR of 5.44 for patients presenting the mutation (95% CI 1.83-16.16). On multivariate analysis, we found a statistically significant increase in risk of recurrence among patients with MSI at D2S123 (HR 5.15; p < 0.05) and more than 2 previous transurethral bladder resections (TURBs) (HR 5.07; p < 0.05) adjusted for tumor stage and grade. Harrell's concordance index revealed an accuracy of 0.74 (p < 0.05). CONCLUSION An association was found between presence BAT26 MSI and female sex, Arg72Pro polymorphism with tumor stage and D2S123 and more than 2 TUR procedures were associated with RFS adjusted to tumor stage and grade.
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Affiliation(s)
- H Garde-García
- Servicio de Urología, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.
| | - E Redondo-González
- Servicio de Urología y Unidad de Biología Molecular del Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria (IdISSC), Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - M Maestro-de Las Casas
- Servicio de Urología y Unidad de Biología Molecular del Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria (IdISSC), Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - C Fernández-Pérez
- Servicio de Urología y Unidad de Biología Molecular del Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria (IdISSC), Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
| | - J Moreno-Sierra
- Servicio de Urología y Unidad de Biología Molecular del Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria (IdISSC), Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain
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12
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Elbehi AM, Anu RI, Ekine-Afolabi B, Cash E. Emerging role of immune checkpoint inhibitors and predictive biomarkers in head and neck cancers. Oral Oncol 2020; 109:104977. [PMID: 32853912 DOI: 10.1016/j.oraloncology.2020.104977] [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: 05/25/2020] [Revised: 07/29/2020] [Accepted: 08/10/2020] [Indexed: 02/07/2023]
Abstract
Head and neck cancers are a group of diverse and heterogeneous tumors, among which squamous cell carcinoma of the head and neck (SCCHN) is the most prevalent. Current treatment modalities have limited efficacy; therefore, new therapies are being actively developed and evaluated. The introduction of immune checkpoint inhibitors (ICIs) has led to a paradigm shift in the management of difficult-to-treat malignancies. In this review, we summarize recent advances in the development of immunotherapies, which are aimed at the functional restoration of the immune system to counteract immune-evasion strategies of cancer cells, and related biomarkers. Monotherapies with ICIs, which primarily target the programmed cell death-1 (PD-1) pathway, have shown promising results in clinical trials of patients with recurrent and metastatic SCCHN. Combinations of ICIs with conventional or virus therapies often have synergistic therapeutic effects, without increased toxicity. As only a small subset of patients respond to immunotherapy, biomarkers are essential for the prediction of treatment response and better selection of patients for ICIs. PD-1 ligand (PD-L1) expression is correlated with response but has several limitations as a predictive marker, as its expression is dynamic and heterogeneous, and the cut-off needs further confirmation. Therefore, tumor mutation burden, gene expression signatures, microsatellite instability, tumor-infiltrating lymphocytes, viral antigens, and the oral microbiota are being investigated as predictive biomarkers. Finally, we delineate other challenges and future prospects for improving patient outcomes, including the major challenge of identifying and validating predictive biomarkers that need to be addressed in future studies.
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Affiliation(s)
- Attia M Elbehi
- School of Care and Health Sciences, University of South Wales, Wales, United Kingdom; Cancer Biology and Therapeutics: High Impact Cancer Research Postgraduate Certificate Program, Harvard Medical School, Boston, MA, USA.
| | - R I Anu
- Cancer Biology and Therapeutics: High Impact Cancer Research Postgraduate Certificate Program, Harvard Medical School, Boston, MA, USA; Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Kerala, India
| | - Bene Ekine-Afolabi
- Cancer Biology and Therapeutics: High Impact Cancer Research Postgraduate Certificate Program, Harvard Medical School, Boston, MA, USA; Founder & CEO, ZEAB Therapeutic, London, United Kingdom
| | - Elizabeth Cash
- Cancer Biology and Therapeutics: High Impact Cancer Research Postgraduate Certificate Program, Harvard Medical School, Boston, MA, USA; Department of Otolaryngology and Communicative Disorders, University of Louisville School of Medicine, Louisville, KY, USA
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13
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Park Y, Kim DW, Hong YJ, Park KU, Nam SK, Na HY, Lee HS, Kim MH, Oh HK, Kang SB. Is elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)-negative/MSI-high colorectal cancer a distinct subtype of the disease? J Surg Oncol 2020; 122:1462-1469. [PMID: 32779222 DOI: 10.1002/jso.26157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 07/26/2020] [Indexed: 11/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Microsatellite instability (MSI) plays a prognostic and predictive role in colorectal cancer (CRC). Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a novel type of MSI, was recently identified. METHODS A retrospective analysis of a prospective cohort database was performed. Patients who attempted curative surgery for MSI-high (MSI-H) CRC and had available testing results of EMAST were included for analysis. The difference in clinical characteristics, immunohistochemistry profile, and 3-year recurrence-free and overall survival between EMAST-negative and EMAST-positive tumors was measured. RESULTS EMAST status was successfully evaluated in 86 cases among patients who received EMAST testing, and only 16.3% (14/86) of these patients were EMAST-negative/MSI-H. Patients with EMAST-negative tumors were younger; their tumors exhibited well differentiation, less venous invasion, and greater mutS homolog 3 expression. There was no distant metastasis or cancer-specific death among EMAST-negative patients. Yet no statistically significant difference was found between the two groups in 3-year overall or recurrence-free survival. CONCLUSIONS Patients with EMAST-negative/MSI-H CRC seem to have different clinicopathological characteristics. Future large-scale studies could clarify the role of EMAST genotype as a sub-classifier of MSI-H CRC.
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Affiliation(s)
- Yeshong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yun Ji Hong
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Kyoung Un Park
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Min Hyun Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Heung-Kwon Oh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
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14
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Ranjbar R, Esfahani AT, Nazemalhosseini-Mojarad E, Olfatifar M, Aghdaei HA, Mohammadpour S. EMAST frequency in colorectal cancer: a meta-analysis and literature review. Biomark Med 2020; 14:1021-1030. [PMID: 32940074 DOI: 10.2217/bmm-2020-0068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 05/21/2020] [Indexed: 01/07/2023] Open
Abstract
Aim: The prognostic and predictive value of Elevated Microsatellite Alterations at Selected Tetranucleotide (EMAST) has been reported in colorectal cancer (CRC). The prevalence of EMAST in CRC varied across the literature. We conducted a meta-analysis to determine the prevalence of EMAST in CRC. Materials & methods: Three international databases including PubMed, ISI and Scopus were searched to identify related articles that described the frequency of EMAST. Results: Analysis was performed on 16 eligible studies including 4922 patients. The overall EMAST prevalence among CRCs patients was 33% (95% CI: 23-43%, I2 = 98%). Conclusion: This study indicated that approximately a third of the CRC patients are diagnosed with EMAST, hereupon EMAST as a prognostic and predictive biomarker should be more studied clinically.
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Affiliation(s)
- Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir T Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Olfatifar
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid A Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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Pećina-Šlaus N, Kafka A, Salamon I, Bukovac A. Mismatch Repair Pathway, Genome Stability and Cancer. Front Mol Biosci 2020; 7:122. [PMID: 32671096 PMCID: PMC7332687 DOI: 10.3389/fmolb.2020.00122] [Citation(s) in RCA: 149] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/25/2020] [Indexed: 01/02/2023] Open
Abstract
The acquisition of genomic instability is one of the key characteristics of the cancer cell, and microsatellite instability (MSI) is an important segment of this phenomenon. This review aims to describe the mismatch DNA repair (MMR) system whose deficiency is responsible for MSI and discuss the cellular roles of MMR genes. Malfunctioning of the MMR repair pathway increases the mutational burden of specific cancers and is often involved in its etiology, sometimes as an influential bystander and sometimes as the main driving force. Detecting the presence of MSI has for a long time been an important part of clinical diagnostics, but has still not achieved its full potential. The MSI blueprints of specific tumors are useful for precize grading, evaluation of cancer chance and prognosis and to help us understand how and why therapy-resistant cancers arise. Furthermore, evidence indicates that MSI is an important predictive biomarker for the application of immunotherapy.
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Affiliation(s)
- Nives Pećina-Šlaus
- Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.,Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anja Kafka
- Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.,Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Iva Salamon
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
| | - Anja Bukovac
- Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.,Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
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16
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The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation. Mol Cell Biol 2020; 40:MCB.00029-20. [PMID: 32284349 DOI: 10.1128/mcb.00029-20] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/07/2020] [Indexed: 12/16/2022] Open
Abstract
Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portend poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the proinflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. In this study, we manipulated three putative nuclear localization (NLS1 to -3) and two potential nuclear export signals (NES1 and -2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, MSH3 with this deletion (Δ27bp MSH3) localizes to the cytoplasm, suggesting that NLS1 function in Δ27bp MSH3 is compromised. Overall, MSH3's shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammation-associated neoplastic processes.
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17
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Li JX, Huang JM, Jiang ZB, Li RZ, Sun A, Lai-Han Leung E, Yan PY. Current Clinical Progress of PD-1/PD-L1 Immunotherapy and Potential Combination Treatment in Non-Small Cell Lung Cancer. Integr Cancer Ther 2020; 18:1534735419890020. [PMID: 31838881 PMCID: PMC7242804 DOI: 10.1177/1534735419890020] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Conventional methods in treating non–small cell lung cancer contain surgery,
chemotherapy, radiotherapy, and targeted therapy, which have various defects.
Recently, with the deeper research on tumor immunity, immunotherapy has made the
breakthrough in the treatment of cancers. Especially developments of programmed
cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the
therapy into a new stage. This review mainly focuses on introducing existing
monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab,
avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1
expression, tumor mutation burden, and microsatellite instability. By
understanding the resistance mechanism of anti-PD-1/L1 blockade, research is
further improving the survival benefit and expanding the benefit population. So,
PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies
clinically. Discussion and comparison of their effectiveness and safety are also
comprehensively reviewed. Meanwhile, we explore the potential, the impact, and
mechanisms of combining traditional Chinese medicine with immunotherapy.
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Affiliation(s)
- Jia-Xin Li
- Macau University of Science and Technology, Macau, People's Republic of China
| | - Ju-Min Huang
- Macau University of Science and Technology, Macau, People's Republic of China
| | - Ze-Bo Jiang
- Macau University of Science and Technology, Macau, People's Republic of China
| | - Run-Ze Li
- Macau University of Science and Technology, Macau, People's Republic of China
| | - Ao Sun
- Macau University of Science and Technology, Macau, People's Republic of China
| | - Elaine Lai-Han Leung
- Macau University of Science and Technology, Macau, People's Republic of China.,Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, People's Republic of China
| | - Pei-Yu Yan
- Macau University of Science and Technology, Macau, People's Republic of China
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18
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Watson MM, Lea D, Gudlaugsson E, Skaland I, Hagland HR, Søreide K. Prevalence of PD-L1 expression is associated with EMAST, density of peritumoral T-cells and recurrence-free survival in operable non-metastatic colorectal cancer. Cancer Immunol Immunother 2020; 69:1627-1637. [PMID: 32314040 PMCID: PMC7347699 DOI: 10.1007/s00262-020-02573-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/07/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Microsatellite instability (MSI) predict response to anti-PD1 immunotherapy in colorectal cancer (CRC). CRCs with MSI have higher infiltration of immune cells related to a better survival. Elevated Microsatellite Alterations at Tetranucleotides (EMAST) is a form of MSI but its association with PD-L1 expression and immune-cell infiltration is not known. METHODS A consecutive, observational cohort of patients undergoing surgery for CRC. EMAST and clinicopathological characteristics were investigated against PD-L1, as well as CD3 and CD8 expression in the invasive margin or tumour centre (Immunoscore). Difference in survival between groups was assessed by log rank test. RESULTS A total of 149 stage I-III CRCs patients, with a median follow up of 60.1 months. Patients with PD-L1+ tumours (7%) were older (median 79 vs 71 years, p = 0.045) and had EMAST+ cancers (OR 10.7, 95% CI 2.2-51.4, p = 0.001). Recurrence-free survival was longer in cancers with PD-L1+ immune cells (HR 0.35, 95% CI 0.16-0.76, p = 0.008, independent of EMAST) and high Immunoscore (HR 0.10, 95% CI 0.01-0.72, p = 0.022). Patients expressing PD-L1 in immune cells had longer disease-specific survival (HR 0.28, 95% CI 0.10-0.77, p = 0.014). CONCLUSIONS Higher Immunoscore (CD3/CD8 cells) and expression of tumour PD-L1 is found in CRCs with EMAST. Lymphocytic infiltrate and peritumoral PD-L1 expression have prognostic value in CRC.
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Affiliation(s)
- Martin M Watson
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Einar Gudlaugsson
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Ivar Skaland
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Kjetil Søreide
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway.
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
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19
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The Clinicopathological Features and Genetic Mutations in Gastric Cancer Patients According to EMAST and MSI Status. Cancers (Basel) 2020; 12:cancers12030551. [PMID: 32120855 PMCID: PMC7139949 DOI: 10.3390/cancers12030551] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 01/22/2023] Open
Abstract
Background: There has been no report regarding the clinicopathological features and genetic mutations regarding elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in gastric cancer (GC). Methods: The correlation among EMAST status, microsatellite instability (MSI) status, mutations of common GC-related genes and 16 DNA repair-associated genes, and the clinicopathological features were analyzed. Results: Among the 360 GC patients enrolled, there were 76 (21.1%) with EMAST+ tumors and 284 with EMAST− tumors, and 59 (16.4%) were MSI-high (MSI-H) tumors, and 301 were microsatellite stable (MSS) tumors. Patients with EMAST+ tumors exhibited an earlier pathological T category and had more genetic mutations in the PI3K/AKT pathway, ARID1A and DNA repair-associated genes than those with EMAST− tumors. Patients with MSI-H tumors have more genetic mutations in the PI3K/AKT pathway and DNA repair-associated genes than those with MSS tumors. In the subgroup analysis for MSI-H GC, EMAST+ tumors were associated with earlier pathological T and N categories, earlier TNM stages, higher frequency of DNA-repair-associated genetic mutations, and a better survival rate than EMAST− tumors. Conclusions:PI3K/AKT pathway mutations may play an important role in EMAST+ and/or MSI-H GC. EMAST+/MSI-H tumors seem to represent a different subtype of gastric cancer from EMAST−/MSI-H tumors.
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20
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Raeker MÖ, Pierre-Charles J, Carethers JM. Tetranucleotide Microsatellite Mutational Behavior Assessed in Real Time: Implications for Future Microsatellite Panels. Cell Mol Gastroenterol Hepatol 2020; 9:689-704. [PMID: 31982570 PMCID: PMC7163322 DOI: 10.1016/j.jcmgh.2020.01.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Fifty percent of colorectal cancers show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and are associated with inflammation, metastasis, and poor patient outcome. EMAST results from interleukin 6-induced nuclear-to-cytosolic displacement of the DNA mismatch repair protein Mutated S Homolog 3, allowing frameshifts of dinucleotide and tetranucleotide but not mononucleotide microsatellites. Unlike mononucleotide frameshifts that universally shorten in length, we previously observed expansion and contraction frameshifts at tetranucleotide sequences. Here, we developed cell models to assess tetranucleotide frameshifts in real time. METHODS We constructed plasmids containing native (AAAG)18 and altered-length ([AAAG]15 and [AAAG]12) human D9S242 locus that placed enhanced green fluorescent protein +1 bp/-1 bp out-of-frame for protein translation and stably transfected into DNA mismatch repair-deficient cells for clonal selection. We used flow cytometry to detect enhanced green fluorescent protein-positive cells to measure mutational behavior. RESULTS Frameshift mutation rates were 31.6 to 71.1 × 10-4 mutations/cell/generation and correlated with microsatellite length (r2 = 0.986, P = .0375). Longer repeats showed modestly higher deletion over insertion rates, with both equivalent for shorter repeats. Accumulation of more deletion frameshifts contributed to a distinct mutational bias for each length (overall: 77.8% deletions vs 22.2% insertions), likely owing to continual deletional mutation of insertions. Approximately 78.9% of observed frameshifts were 1 AAAG repeat, 16.1% were 2 repeats, and 5.1% were 3 or more repeats, consistent with a slipped strand mispairing mutation model. CONCLUSIONS Tetranucleotide frameshifts show a deletion bias and undergo more than 1 deletion event via intermediates, with insertions converted into deletions. Tetranucleotide markers added to traditional microsatellite instability panels will be able to determine both EMAST and classic microsatellite instability, but needs to be assessed by multiple markers to account for mutational behavior and intermediates.
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Affiliation(s)
- Maide Ö Raeker
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jovan Pierre-Charles
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - John M Carethers
- Department of Human Genetics and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
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21
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Watson MM, Lea D, Hagland HR, Søreide K. Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) Is Not Attributed to MSH3 Loss in Stage I-III Colon cancer: An Automated, Digitalized Assessment by Immunohistochemistry of Whole Slides and Hot Spots. Transl Oncol 2019; 12:1583-1588. [PMID: 31677491 PMCID: PMC6930943 DOI: 10.1016/j.tranon.2019.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/08/2019] [Accepted: 08/14/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION EMAST is a poorly understood form of microsatellite instability (MSI) in colorectal cancer (CRC) for which loss of MSH3 has been proposed as the underlying mechanism, based on experimental studies. We aimed to evaluate whether MSH3 loss is associated with EMAST in CRC. METHODS A consecutive cohort of patients with stage I-III CRC. Digital image analysis using heatmap-derived hot spots investigated MSH3 expression by immunohistochemistry. Fragment analysis of multiplex PCR was used to assess MSI and EMAST, and results cross-examined with MSH3 protein expression. RESULTS Of 152 patients, EMAST was found in 50 (33%) and exclusively in the colon. Most EMAST-positive cancers had instability at all 5 markers, and EMAST overlapped with MSI-H in 42/50 cases (84%). The most frequently altered tetranucleotide markers were D8S321 (38.2% of tumors) and D20S82 (34.4%). Subjective evaluation of MSH3 expression by IHC in tumor found ≤10% negative tumor cells in all samples, most being ≤5% negative. Digital analysis improved the detection but showed a similar spread of MSH3 loss (range 0.1-15.7%, mean 2.2%). Hotspot MSH3 negativity ranged between 0.1 to 95.0%, (mean 8.6%) with significant correlation with the whole slide analysis (Spearman's rho=0.677 P<.001). Loss of MSH3 expression did not correlate with EMAST. CONCLUSIONS In a well-defined cohort of patients with CRC, loss of MSH3 was not associated with EMAST. Further investigation into the mechanisms leading to EMAST in CRC is needed.
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Affiliation(s)
- Martin M Watson
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Norway
| | - Kjetil Søreide
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Medicine, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway
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22
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Watson MM, Kanani A, Lea D, Khajavi RB, Søreide JA, Kørner H, Hagland HR, Søreide K. Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) in Colorectal Cancer is Associated with an Elderly, Frail Phenotype and Improved Recurrence-Free Survival. Ann Surg Oncol 2019; 27:1058-1067. [PMID: 31686344 DOI: 10.1245/s10434-019-08048-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a poorly investigated form of microsatellite instability (MSI) in colorectal cancer (CRC). OBJECTIVE The aim of this study was to investigate the clinicopathological features of EMAST in CRC and its relation to outcome. METHODS A population-based, consecutive cohort of surgically treated stage I-III CRC patients investigated for high-frequency MSI (MSI-H) and EMAST. Clinicopathological differences were reported as odds ratios (OR) and survival was presented as hazard ratios (HR) with 95% confidence intervals (CIs). RESULTS Of 161 patients included, 25% were aged > 79 years. There was a large overlap in the prevalence of EMAST (31.7%) and MSI-H (27.3%) [82.4% of EMAST were also MSI-H]. EMAST had the highest prevalence in the proximal colon (OR 15.9, 95% CI 5.6-45.1; p < 0.001) and in women (OR 4.1, 95% CI 1.9-8.6; p < 0.001), and were poorly differentiated (OR 5.0, 95% CI 2.3-10.7; p < 0.001). Compared with EMAST-negative patients, EMAST-positive patients were older (median age 77 vs. 69 years; p < 0.001), leaner (median weight 67.5 vs. 77 kg; p = 0.001), had significantly higher rates of hypoalbuminemia (24% vs. 6%; OR 2.3, 95% CI 1.5-3.6; p = 0.002) and anemia (45% vs. 20%; OR 3.3, 95% CI 1.6-6.8; p = 0.001), and had elevated preoperative C-reactive protein (CRP) levels (51% vs. 34%; OR 1.9, 95% CI 1.0-3.9; p = 0.046). Improved recurrence-free survival was found in both MSI-H and EMAST subtypes. In multivariable analysis, node status (pN +), together with elevated CRP and MSI-positive, were the strongest prognostic factors for recurrence-free survival. CONCLUSIONS EMAST in CRC is associated with an older, leaner, and frailer phenotype with a lower risk of recurrence. The relevance of, and putative mechanisms to, EMAST warrants further investigation.
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Affiliation(s)
- Martin M Watson
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Arezo Kanani
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Ramesh B Khajavi
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Jon Arne Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Hartwig Kørner
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Technology, University of Stavanger, Stavanger, Norway
| | - Kjetil Søreide
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway. .,Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway. .,Department of Clinical Medicine, University of Bergen, Bergen, Norway.
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23
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Kuan TC, Chang SC, Lin JK, Lin TC, Yang SH, Jiang JK, Chen WS, Wang HS, Lan YT, Lin CC, Lin HH, Huang SC. Prognosticators of Long-Term Outcomes of TNM Stage II Colorectal Cancer: Molecular Patterns or Clinicopathological Features. World J Surg 2019; 43:3207-3215. [PMID: 31515570 DOI: 10.1007/s00268-019-05158-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with stage II colorectal cancer (CRC) have a higher risk of recurrence when they have certain risk factors, including clinical and pathological patterns. However, as the prognostic role of molecular patterns for stage II disease is still unclear, this study aimed to investigate it. METHODS A total of 509 patients with stage II CRC were enrolled, and all clinical, pathological, and molecular data were collected. Molecular patterns included microsatellite instability (MSI); elevated microsatellite alterations at selected tetranucleotides (EMAST) status; and expression of RAS/RAF genes, genes of the APC pathway, and other gene mutations. The endpoints were oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), local recurrence (LR), and distant recurrence (DR). Cox regression analysis was used. RESULTS Numerous molecular patterns influenced the oncological outcomes on univariate analysis, but no variable reached significance in LR. On multivariate analysis, a mucinous component (MC) > 50% (P < 0.01) was significant for OS and CSS. Lymphovascular invasion (LVI; P< 0.01), MC > 50% (P < 0.01), and EMAST-H (P = 0.02) significantly influenced DFS, whereas LVI (P < 0.01), MC > 50% (P < 0.01), and TP53 mutation (P = 0.02) were significant for DR. CONCLUSIONS In this study, MSI, EMAST, and RAS/RAF alterations did not influence the oncological outcomes. Overall, LVI and MC were two significant prognostic factors for DFS and DR. Thus, the histopathology, rather than the genes, plays a major role in the prognosis of patients with stage II CRC.
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Affiliation(s)
- Tai-Chuan Kuan
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Ching Chang
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan. .,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Jen-Kou Lin
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Tzu-Chen Lin
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shung-Haur Yang
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,National Yang-Ming University Hospital, Yilan, Taiwan
| | - Jeng-Kae Jiang
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Shone Chen
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Huann-Sheng Wang
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yuan-Tzu Lan
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Chi Lin
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hung-Hsin Lin
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sheng-Chieh Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Veteran General Hospital, No. 201, Sec. 2., Shipai Rd., Beitou District, Taipei, 11217, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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24
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Tamura K, Kaneda M, Futagawa M, Takeshita M, Kim S, Nakama M, Kawashita N, Tatsumi-Miyajima J. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol 2019; 24:999-1011. [PMID: 31273487 DOI: 10.1007/s10147-019-01494-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022]
Abstract
Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.
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Affiliation(s)
- Kazuo Tamura
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan.
| | - Motohide Kaneda
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
| | - Mashu Futagawa
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
| | - Miho Takeshita
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
| | - Sanghyuk Kim
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
| | - Mina Nakama
- Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan
| | - Norihito Kawashita
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
| | - Junko Tatsumi-Miyajima
- Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
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25
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Zekri ARN, Khaled HM, Mohammed MB, Diab FM, Abdellateif MS, El Deeb S, Badr AM, Mohanad M, Abdallah SO, Bahnassy AA. Microsatellite instability profiling in Egyptian bladder cancer patients: A pilot study. Curr Probl Cancer 2019; 43:100472. [PMID: 30929752 DOI: 10.1016/j.currproblcancer.2019.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/19/2019] [Indexed: 12/15/2022]
Abstract
Microsatellite alterations have been implicated in the pathogenesis of many cancers; however, they are still not well addressed in the bladder cancer (BC) of Egyptian population. We assessed microsatellite instability (MSI) profile and loss of heterozygosity (LOH) using 13 microsatellite markers in tumor tissue samples and urine sediments obtained from 30 Egyptian patients with BC. The concordance between MSI in tumor tissue and urine samples was determined, and correlated to relevant clinicopathologic features. We found that MSI was more frequent than LOH (100% and 46.7%, respectively). D16S310, MBP, and IFN-α showed the highest MSI frequency in urine samples (70%, 70%, and 66.67%, respectively), while MBP, ACTBP2, and D9S171 (66.67%, 63.33%, and 60%, respectively) were the most frequently detected in tumor tissues. All assessed MSI markers correlated significantly with pathologic subtype (being more frequent in TCC) and with hematuria. The concordance between tissue and urine samples was statistically significant for D16S476, D9S171, FGA, and ACTBP2 (P = 0.04, 0.015, 0.02, and 0.007, respectively). When we combined D16S476 and D9S171, the sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of BC were 80.0%, 75.0%, 82.8%, and 71.4%, respectively. Accordingly, we concluded that MSI in urine sediments could be a potential tool for the diagnosis of BC.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Hussein M Khaled
- Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Mai B Mohammed
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Fatma M Diab
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Somaya El Deeb
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Abeer M Badr
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Marwa Mohanad
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October, Egypt
| | - Sanaa O Abdallah
- Inorganic Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
| | - Abeer A Bahnassy
- Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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26
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Drake TM, Søreide K. Cancer epigenetics in solid organ tumours: A primer for surgical oncologists. Eur J Surg Oncol 2019; 45:736-746. [PMID: 30745135 DOI: 10.1016/j.ejso.2019.02.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 01/29/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023] Open
Abstract
Cancer is initiated through both genetic and epigenetic alterations. The end-effect of such changes to the DNA machinery is a set of uncontrolled mechanisms of cell division, invasion and, eventually, metastasis. Epigenetic changes are now increasingly appreciated as an essential driver to the cancer phenotype. The epigenetic regulation of cancer is complex and not yet fully understood, but application of epigenetics to clinical practice and in cancer research has the potential to improve cancer care. Epigenetics changes do not cause changes in the DNA base-pairs (and, hence, does not alter the genetic code per se) but rather occur through methylation of DNA, by histone modifications, and, through changes to chromatin structure to alter genetic expression. Epigenetic regulators are characterized as writers, readers or erasers by their mechanisms of action. The human epigenome is influenced from cradle to grave, with internal and external life-time exposure influencing the epigenetic marks that may act as modifiers or drivers of carcinogenesis. Preventive and public health strategies may follow from better understanding of the life-time influence of the epigenome. Epigenetics may be used to define risk, to investigate mechanisms of carcinogenesis, to identify biomarkers, and to identify novel therapeutic options. Epigenetic alterations are found across many solid cancers and are increasingly making clinical impact to cancer management. Novel epigenetic drugs may be used for a more tailored and specific response to treatment of cancers. We present a primer on epigenetics for surgical oncologists with examples from colorectal cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma.
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Affiliation(s)
- Thomas M Drake
- Department of Clinical Surgery, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK
| | - Kjetil Søreide
- Department of Clinical Surgery, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK; Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
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27
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Torshizi Esfahani A, Seyedna SY, Nazemalhosseini Mojarad E, Majd A, Asadzadeh Aghdaei H. MSI-L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients. J Cell Physiol 2018; 234:13128-13136. [PMID: 30549036 DOI: 10.1002/jcp.27983] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 11/21/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) is a prognostic marker in colorectal cancer (CRC). The biological significance of MSI-low (MSI-L) phenotype and its differences with microsatellite stable (MSS) phenotype remains unclear. The aim of this study is indicating the role of mononucleotide repeat in identifying MSI-L and revealing the association of MSI-L with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and oncologic outcome in CRC patients. METHODS MSI and EMAST status were analyzed using three quasimonomorphic panel (BAT-25, BAT-26, and NR-27) and five tetranucleotide repeats (D20S82, D20S85, D9S242, D8S321, and MYCL1), respectively, by capillary electrophoresis method without the need to fluorescent primers. The associations of MSI status with clinicopathological features, EMAST status, metastasis, and overall survival (OS) were investigated. RESULTS Among 159 CRC patient 22.0% were MSI-H, 40.3% were MSS, 37.7% were MSI-L, and 41.5% showed EMAST + phenotype. MSI-L were associated with advanced stages, EMAST+ tumors and worse OS ( p ≤ 0.001). Metastasis was relatively common in MSI-L/EMAST + CRCs and BAT-25 were the most unstable marker in these tumors. CONCLUSIONS MSI-L tumors have different clinicopathological features from MSS and MSI-H tumors. The MSI-L phenotype is a worse prognostic biomarker in CRC and when accompanied by EMAST could be a predictor for metastasis.
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Affiliation(s)
- Amir Torshizi Esfahani
- Department of Biology, Faculty of Biological Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Seyed Yoosef Seyedna
- Department of Biology, Faculty of Biological Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Ehsan Nazemalhosseini Mojarad
- Department of Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Majd
- Department of Molecular Medicine, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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28
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Liu SA, Wang CC, Jiang RS, Wang WY, Lin JC. Genetic analysis of surgical margins in oral cavity cancer. Br J Surg 2018; 105:e142-e149. [PMID: 29341160 DOI: 10.1002/bjs.10693] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/05/2017] [Accepted: 08/14/2017] [Indexed: 11/11/2022]
Abstract
BACKGROUND A histological, tumour-free surgical margin does not guarantee recurrence-free survival in patients with cancer. This study investigated the association between microsatellite alteration in tumour-free surgical margins and local recurrence in patients with oral cavity squamous cell carcinoma. METHODS Patients with histologically confirmed oral cavity squamous cell carcinoma were enrolled in this prospective study. Cancerous specimens, corresponding surgical margins and peripheral blood were obtained. Microsatellite alteration was investigated using six dinucleotide microsatellite markers. All samples were amplified by PCR, followed by automatic fragment analysis. RESULTS Microsatellite alteration was identified in 100 specimens (69·0 per cent) from 145 patients. Among them, 85 specimens carried loss of heterozygosity, whereas 55 had microsatellite instability (MSI). Patients with MSI at the surgical margin had a higher risk of local recurrence on multivariable analysis (odds ratio 7·17, 95 per cent c.i. 3·49 to 14·73). CONCLUSION Molecular assessment of surgical margins can help identify patients at risk of local recurrence.
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Affiliation(s)
- S A Liu
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - C C Wang
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taichung, Taiwan
| | - R S Jiang
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - W Y Wang
- Department of Nursing, HungKuang University, Taichung, Taiwan
| | - J C Lin
- Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taichung, Taiwan
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29
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Mori T, Hamaya Y, Uotani T, Yamade M, Iwaizumi M, Furuta T, Miyajima H, Osawa S, Sugimoto K. Prevalence of elevated microsatellite alterations at selected tetranucleotide repeats in pancreatic ductal adenocarcinoma. PLoS One 2018; 13:e0208557. [PMID: 30532127 PMCID: PMC6285458 DOI: 10.1371/journal.pone.0208557] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/19/2018] [Indexed: 01/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) prognosis remains poor even after complete resection owing to no valuable biomarkers for recurrence and chemosensitivity. Tumors not expressing MSH3 show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). EMAST reportedly occurs in several tumors. In colorectal cancer (CRC), EMAST was reportedly correlated with 5-fluorouracil (5-FU) sensitivity. However, EMAST prevalence in PDAC and its significance as a prognostic biomarker are unknown. This study aimed to investigate EMAST prevalence in PDAC and the associations between EMAST and pathological factors, EMAST and prognosis, and EMAST and MSH3 expression via immunohistochemistry (IHC). We assessed 40 PDAC patients undergoing surgery. Genomic DNA was extracted from tumors and normal tissues. EMAST and microsatellite instability-high (MSI-H) were analyzed using five polymorphic tetranucleotide markers and five mononucleotide markers, respectively. Tumor sections were stained for MSH3, and staining intensity was evaluated via the Histoscore (H-score). Eighteen of 40 (45%) PDAC patients were EMAST-positive; however, none were MSI-H-positive. Clinicopathological characteristics including overall survival (OS) and recurrence-free survival (RFS) were not significantly different between EMAST-positive and EMAST-negative patients (P = 0.45, 0.98 respectively). IHC was performed to evaluate MSH3 protein expression levels for the PDAC tissue specimens. H-scores of EMAST-positive patients ranged from 0 to 300 (median, 40) and those of EMAST-negative patients ranged from 0 to 300 (median, 170). MSH3 protein was not significantly downregulated in EMAST-positive patients (P = 0.07). This study is a preliminary study and the number of cases investigated was small, and thus, study of a larger cohort will reveal the clinical implication of EMAST.
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Affiliation(s)
- Taiki Mori
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
- * E-mail:
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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30
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Mitchell ML, Leveille MP, Solecki RS, Tran T, Cannon B. Sequence-Dependent Effects of Monovalent Cations on the Structural Dynamics of Trinucleotide-Repeat DNA Hairpins. J Phys Chem B 2018; 122:11841-11851. [PMID: 30441902 DOI: 10.1021/acs.jpcb.8b07994] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Repetitive trinucleotide DNA sequences at specific genetic loci are associated with numerous hereditary, neurodegenerative diseases. The propensity of single-stranded domains containing these sequences to form secondary structure via extensive self-complementarity disrupts normal DNA processing to create genetic instabilities. To investigate these intrastrand structural dynamics, a DNA hairpin system was devised for single-molecule fluorescence study of the folding kinetics and energetics for secondary structure formation between two interacting, repetitive domains with specific numbers of the same trinucleotide motif (CXG), where X = T or A. Single-molecule fluorescence resonance energy transfer (smFRET) data show discrete conformational transitions between unstructured and closed hairpin states. The lifetimes of the closed hairpin states correlate with the number of repeats, with (CTG) N/(CTG) N domains maintaining longer-lived, closed states than equivalent-sized (CAG) N/(CAG) N domains. NaCl promotes similar degree of stabilization for the closed hairpin states of both repeat sequences. Temperature-based, smFRET experiments reveal that NaCl favors hairpin closing for (CAG) N/(CAG) N by preordering single-stranded repeat domains to accelerate the closing transition. In contrast, NaCl slows the opening transition of CTG hairpins; however, it promotes misfolded conformations that require unfolding. Energy diagrams illustrate the distinct folding pathways of (CTG) N and (CAG) N repeat domains and identify features that may contribute to their gene-destabilizing effects.
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Affiliation(s)
- Marisa L Mitchell
- Department of Physics , Loyola University Chicago , Chicago , Illinois 60660 , United States
| | - Michael P Leveille
- Department of Physics , Loyola University Chicago , Chicago , Illinois 60660 , United States
| | - Roman S Solecki
- Department of Physics , Loyola University Chicago , Chicago , Illinois 60660 , United States
| | - Thao Tran
- Department of Physics , Loyola University Chicago , Chicago , Illinois 60660 , United States
| | - Brian Cannon
- Department of Physics , Loyola University Chicago , Chicago , Illinois 60660 , United States
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31
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A new method for discovering EMAST sequences in animal models of cancer. Sci Rep 2018; 8:13764. [PMID: 30214002 PMCID: PMC6137214 DOI: 10.1038/s41598-018-32057-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/31/2018] [Indexed: 01/28/2023] Open
Abstract
Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) occur in up to 60% of colorectal cancers and may associate with aggressive and advanced disease in patients. Although EMAST occurs in many cancer types, current understanding is limited due to the lack of an animal model. Reported here is the design and implementation of an algorithm for detecting EMAST repeats in mice. This algorithm incorporates properties of known human EMAST sequences to identify repeat sequences in animal genomes and was able to identify EMAST-like sequences in the mouse. Seven of the identified repeats were analyzed further in a colon cancer mouse model and six of the seven displayed EMAST instability characteristic of that seen in human colorectal cancers. In conclusion, the algorithm developed successfully identified EMAST repeats in an animal genome and, for the first time, EMAST has been shown to occur in a mouse model of colon cancer.
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32
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McCrea EM, Lee DK, Sissung TM, Figg WD. Precision medicine applications in prostate cancer. Ther Adv Med Oncol 2018; 10:1758835918776920. [PMID: 29977347 PMCID: PMC6024288 DOI: 10.1177/1758835918776920] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/13/2018] [Indexed: 12/24/2022] Open
Abstract
Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.
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Affiliation(s)
- Edel M. McCrea
- Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Daniel K. Lee
- Medical Oncology Service, and the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tristan M. Sissung
- Clinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - William D. Figg
- Clinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville Pike, Bldg 10/Room 5A01, Bethesda, MD 20892, USA
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33
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Koi M, Okita Y, Carethers JM. Fusobacterium nucleatum Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations. J Anus Rectum Colon 2018; 2:37-46. [PMID: 30116794 PMCID: PMC6090547 DOI: 10.23922/jarc.2017-055] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 01/30/2018] [Indexed: 12/13/2022] Open
Abstract
It has been recently reported that the population of Fusobacterium, particularly Fusobacterium nucleatum (Fn), is overrepresented in colorectal cancers and adenomas. The promoting effects of Fn infection on adenoma and/or carcinoma formation have been shown in ApcMin/+mice. Characteristics of Fn-associated CRC were identified through studies using human CRC cohorts, and include right-sided colon location, CpG island methylation phenotype-high (CIMP-H), high level of microsatellite instability (MSI-H), and poor patient prognosis. A subset of Fn-associated CRC exhibits a low level of microsatellite instability (MSI-L) and elevated microsatellite alterations in selected tetra-nucleotide repeats (EMAST) induced by translocation of MSH3 from the nucleus to the cytoplasm in response to oxidative DNA damage or inflammatory signals. The association between CIMP/MSI-H and Fn-infection can be explained by the role of the mismatch repair (MMR) protein complex formed between MSH2 and MSH6 (MutSα) to repair aberrant bases generated by ROS to form 7,8-dihydro-8-oxo-guanine (8-oxoG). Clustered 8-oxoGs formed at CpG-rich regions including promoters by ROS is refractory to base excision repair (BER). Under these conditions, MutSα initiates repair in cooperation with DNA methyltransferases (DNMTs) and the polycomb repressive complex 4 (PRC4). DNMTs at damaged sites methylate CpG islands to repress transcription of target genes and promote repair reactions. Thus, continuous generation of ROS through chronic Fn infection may initiate 1) CIMP-positive adenoma and carcinoma in an MSH2/MSH6-dependent manner, and/or 2) MSI-L/EMAST CRC in an MSH3-dependent manner. The poor prognosis of Fn-associated CRC can be explained by Fn-induced immune-evasion and/or chemo-resistance.
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Affiliation(s)
- Minoru Koi
- Division of Gastroenterology, Department of Internal Medicine, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yoshiki Okita
- Division of Gastroenterology, Department of Internal Medicine, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
| | - John M Carethers
- Division of Gastroenterology, Department of Internal Medicine, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
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34
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Koi M, Tseng-Rogenski SS, Carethers JM. Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer. World J Gastrointest Oncol 2018; 10:1-14. [PMID: 29375743 PMCID: PMC5767788 DOI: 10.4251/wjgo.v10.i1.1] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 11/29/2017] [Accepted: 12/06/2017] [Indexed: 02/05/2023] Open
Abstract
Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.
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Affiliation(s)
- Minoru Koi
- Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368, United States
| | - Stephanie S Tseng-Rogenski
- Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368, United States
| | - John M Carethers
- Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368, United States
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35
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Pećina-Šlaus N, Kafka A, Bukovac A, Vladušić T, Tomas D, Hrašćan R. Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma. Tumour Biol 2017; 39:1010428317705791. [PMID: 28705114 DOI: 10.1177/1010428317705791] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ2 = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.
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Affiliation(s)
- Nives Pećina-Šlaus
- 1 Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,2 Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anja Kafka
- 1 Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,2 Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anja Bukovac
- 1 Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,2 Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Tomislav Vladušić
- 3 Department of Biochemical Engineering, Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia
| | - Davor Tomas
- 4 Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.,5 University Hospital "Sisters of Charity," Zagreb, Croatia
| | - Reno Hrašćan
- 3 Department of Biochemical Engineering, Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia
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36
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A molecular portrait of microsatellite instability across multiple cancers. Nat Commun 2017; 8:15180. [PMID: 28585546 PMCID: PMC5467167 DOI: 10.1038/ncomms15180] [Citation(s) in RCA: 434] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 03/03/2017] [Indexed: 12/30/2022] Open
Abstract
Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy. Some cancers with DNA mismatch repair deficiency display microsatellite instability. Here the authors analyse twenty three cancer types at the exome and whole-genome level, and identify loci with recurrent microsatellite instability that could be used to identify patients who would benefit from immunotherapy.
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37
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Veen T, Søreide K. Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis? World J Gastrointest Oncol 2017; 9:98-104. [PMID: 28344745 PMCID: PMC5348630 DOI: 10.4251/wjgo.v9.i3.98] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/25/2016] [Accepted: 12/28/2016] [Indexed: 02/05/2023] Open
Abstract
In resectable colorectal liver metastasis (CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases (both resectable and non-resectable) and the shift in indication from “what is taken out” (e.g., how much liver has to be resected) to “what is left behind” (that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.
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38
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Lin JC, Wang CC, Jiang RS, Wang WY, Liu SA. Impact of microsatellite alteration in surgical margins on local recurrence in oral cavity cancer patients. Eur Arch Otorhinolaryngol 2016; 274:431-439. [PMID: 27430224 DOI: 10.1007/s00405-016-4215-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 07/13/2016] [Indexed: 10/21/2022]
Abstract
The aim of this study was to investigate the association between microsatellite alteration in the surgical margins and local recurrence of oral cavity squamous cell carcinoma patients. Surgical specimens confirmed by pathological examination and corresponding surgical margins were collected from 120 oral cavity squamous cell carcinoma patients. Ten microsatellite markers were examined in the tumor specimens and paired surgical margins, which proved to be negative on pathological assessment. The specimens and surgical margins were amplified by polymerase chain reaction followed by computerized analysis. Forty-two specimens (35.0 %) with microsatellite instability (MSI) in at least one marker were found, and more than half of the specimens (n = 73, 60.8 %) had loss of heterozygosity (LOH) in at least one marker. Although MSI and LOH were not associated with the prognosis of oral cavity squamous cell carcinoma patients, presence of MSI in the tumor-free surgical margins increased the risk of local recurrence (hazard ratio: 9.549; 95 % confidence interval: 4.143-22.01). Genetic analysis of tumor-free surgical margins is a useful tool for identifying oral cavity squamous cell carcinoma patients who are vulnerable to local recurrence.
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Affiliation(s)
- Jin-Ching Lin
- Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chen-Chi Wang
- Department of Otolaryngology, Taichung Veterans General Hospital, No. 1650, Sec 4, Taiwan Boulevard, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Rong-San Jiang
- Department of Otolaryngology, Taichung Veterans General Hospital, No. 1650, Sec 4, Taiwan Boulevard, Taichung, Taiwan
| | - Wen-Yi Wang
- Department of Nursing, HungKuang University, Taichung, Taiwan
| | - Shih-An Liu
- Department of Otolaryngology, Taichung Veterans General Hospital, No. 1650, Sec 4, Taiwan Boulevard, Taichung, Taiwan. .,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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39
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Søreide K, Watson MM, Lea D, Nordgård O, Søreide JA, Hagland HR. Assessment of clinically related outcomes and biomarker analysis for translational integration in colorectal cancer (ACROBATICC): study protocol for a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastasis. J Transl Med 2016; 14:192. [PMID: 27357108 PMCID: PMC4928276 DOI: 10.1186/s12967-016-0951-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 06/21/2016] [Indexed: 02/08/2023] Open
Abstract
Background More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis. Methods An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases. Long-term outcomes will be cancer-specific survival, recurrence-free survival and overall survival at 5 years from diagnosis. Beyond routine clinicopathological and anthropometric characteristics and laboratory and biochemistry results, the project allows for additional blood samples and fresh-frozen tumour and normal tissue for investigation of circulating tumour cells (CTCs) and novel biomarkers (e.g. immune cells, microRNAs etc.). Tumour specimens will be investigated by immunohistochemistry in full slides. Extracted DNA/RNA will be analysed for genomic markers using specific PCR techniques and next-generation sequencing (NGS) panels. Flow cytometry will be used to characterise biomarkers in blood. Collaboration is open and welcomed, with particular interest in mutual opportunities for validation studies. Status and perspectives The project is ongoing and recruiting at an expected rate of 120–150 patients per year, since January 2013. A project on circulating tumour cells (CTCs) has commenced, with analysis being prepared. Investigating molecular classes beyond the TNM staging is under way, including characteristics of microsatellite instability (MSI) and elevated microsatellite alterations in selected tetranucleotides (EMAST). Hot spot panels for known mutations in CRC are being investigated using NGS. Immune-cell characteristics are being performed by IHC and flow cytometry in tumour and peripheral blood samples. The project has ethical approval (REK Helse Vest, #2012/742), is financially supported with a Ph.D.-Grant (EMAST project; Folke Hermansen Cancer Fund) and a CTC-project (Norwegian Research Council; O. Nordgård). The ACROBATICC clinical and molecular biobank repository will serve as a long-term source for novel exploratory analysis and invite collaborators for mutual validation of promising biomarker results. The project aims to generate results that can help better discern prognostic groups in stage II/III cancers; explore prognostic and predictive biomarkers, and help detail the biology of colorectal liver metastasis for better patient selection and tailored treatment. The project is registered at http://www.ClinicalTrials.gov NCT01762813.
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Affiliation(s)
- Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway. .,Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway. .,Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Martin M Watson
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway.,Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Oddmund Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Jon Arne Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Centre of Organelle Research (CORE), University of Stavanger, Stavanger, Norway
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Watson MM, Lea D, Rewcastle E, Hagland HR, Søreide K. Elevated microsatellite alterations at selected tetranucleotides in early-stage colorectal cancers with and without high-frequency microsatellite instability: same, same but different? Cancer Med 2016; 5:1580-7. [PMID: 27061136 PMCID: PMC4944885 DOI: 10.1002/cam4.709] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 02/26/2016] [Accepted: 02/29/2016] [Indexed: 12/21/2022] Open
Abstract
Microsatellite instability (MSI) is associated with better prognosis in colorectal cancer (CRC). Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a less‐understood form of MSI. Here, we aim to investigate the role of EMAST in CRC±MSI related to clinical and tumor‐specific characteristics. A consecutive, population‐based series of stage I–III colorectal cancers were investigated for MSI and EMAST using PCR primers for 10 microsatellite markers. Of 151 patients included, 33 (21.8%) had MSI and 35 (23.2%) were EMAST+, with an overlap of 77% for positivity, (odds ratio [OR] 61; P < 0.001), and 95% for both markers being negative. EMAST was more prevalent in colon versus rectum (86% vs. 14%, P = 0.004). EMAST+ cancers were significantly more frequent in proximal colon (77 vs. 23%, P = 0.004), had advanced t‐stage (T3–4 vs. T1–2 in 94% vs. 6%, respectively; P = 0.008), were larger (≥5 cm vs. <5 cm in 63% and 37%, respectively; P = 0.022) and had poorly differentiated tumor grade (71 vs. 29%, P < 0.01). Furthermore, EMAST+ tumors had a higher median number of harvested lymph nodes than EMAST− (11 vs. 9 nodes; P = 0.03). No significant association was found between EMAST status and age, gender, presence of distant metastases or metastatic lymph nodes, and overall survival. A nonsignificant difference toward worse survival in node‐negative colon cancers needs confirmation in larger cohorts. EMAST+ cancers overlap and share features with MSI+ in CRC. Overall, survival was not influenced by the presence of EMAST, but may be of importance in subgroups such as node‐negative disease of the colon.
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Affiliation(s)
- Martin M Watson
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Gastrointestinal Translational Research Unit, Molecular Laboratory, Hillevåg, Stavanger University Hospital, Stavanger, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Molecular Laboratory, Hillevåg, Stavanger University Hospital, Stavanger, Norway.,Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Emma Rewcastle
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Molecular Laboratory, Hillevåg, Stavanger University Hospital, Stavanger, Norway.,Centre for Organelle Research (CORE), University of Stavanger, Stavanger, Norway
| | - Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Gastrointestinal Translational Research Unit, Molecular Laboratory, Hillevåg, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Søreide K, Watson MM, Hagland HR. Deciphering the Molecular Code to Colorectal Liver Metastasis Biology Through Microsatellite Alterations and Allelic Loss: The Good, the Bad, and the Ugly. Gastroenterology 2016; 150:811-4. [PMID: 26924094 DOI: 10.1053/j.gastro.2016.02.060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Martin M Watson
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway; Centre of Organelle Research (CORE), University of Stavanger, Stavanger, Norway
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Koi M, Garcia M, Choi C, Kim HR, Koike J, Hemmi H, Nagasaka T, Okugawa Y, Toiyama Y, Kitajima T, Imaoka H, Kusunoki M, Chen YH, Mukherjee B, Boland CR, Carethers JM. Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. Gastroenterology 2016; 150:944-55. [PMID: 26752111 PMCID: PMC4808397 DOI: 10.1053/j.gastro.2015.12.032] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 12/20/2015] [Accepted: 12/22/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. METHODS We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. RESULTS LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P = .01). CONCLUSIONS E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.
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Affiliation(s)
- Minoru Koi
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - C Richard Boland
- Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
| | - John M Carethers
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Microsatellite alteration in head and neck squamous cell carcinoma patients from a betel quid-prevalent region. Sci Rep 2016; 6:22614. [PMID: 27009367 PMCID: PMC4806345 DOI: 10.1038/srep22614] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 02/17/2016] [Indexed: 11/23/2022] Open
Abstract
We investigated the frequency of microsatellite alteration and their impact on survival in head and neck squamous cell carcinoma patients from an endemic betel quid chewing area. We collected 116 head and neck squamous cell carcinoma specimens along with corresponding surgical margins which were confirmed by pathological examination. Ten oligonucleotide markers were chosen for the assessment of microsatellite alteration. The specimens were amplified by polymerase chain reaction followed by automatic fragment analysis. There were 44 specimens (37.9%) with microsatellite instability (MSI) in at least one marker while more than half of the specimens (n = 68, 58.6%) had loss of heterozygosity (LOH) in at least one marker. Though MSI/LOH was not correlated with the survival of head and neck squamous cell carcinoma patients, presence of MSI in the tumor-free surgical margins was associated with local recurrence (odds ratio: 15.14; 95% confidence interval: 6.451 ~ 35.53; P < 0.001). Genomic assessment of surgical margin can help surgeons to identify head and neck squamous cell carcinoma patients who are at risk of developing local recurrence in a betel quid-prevalent region.
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Ferguson LR, Chen H, Collins AR, Connell M, Damia G, Dasgupta S, Malhotra M, Meeker AK, Amedei A, Amin A, Ashraf SS, Aquilano K, Azmi AS, Bhakta D, Bilsland A, Boosani CS, Chen S, Ciriolo MR, Fujii H, Guha G, Halicka D, Helferich WG, Keith WN, Mohammed SI, Niccolai E, Yang X, Honoki K, Parslow VR, Prakash S, Rezazadeh S, Shackelford RE, Sidransky D, Tran PT, Yang ES, Maxwell CA. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol 2015; 35 Suppl:S5-S24. [PMID: 25869442 PMCID: PMC4600419 DOI: 10.1016/j.semcancer.2015.03.005] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 03/08/2015] [Accepted: 03/13/2015] [Indexed: 02/06/2023]
Abstract
Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.
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Affiliation(s)
| | - Helen Chen
- Department of Pediatrics, University of British Columbia, Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Vancouver, Canada
| | - Andrew R Collins
- Department of Nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Marisa Connell
- Department of Pediatrics, University of British Columbia, Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Vancouver, Canada
| | - Giovanna Damia
- Department of Oncology, Instituti di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Santanu Dasgupta
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, United States
| | | | - Alan K Meeker
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates; Faculty of Science, Cairo University, Cairo, Egypt
| | - S Salman Ashraf
- Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Katia Aquilano
- Department of Biology, Università di Roma Tor Vergata, Rome, Italy
| | - Asfar S Azmi
- Department of Biology, University of Rochester, Rochester, United States
| | - Dipita Bhakta
- School of Chemical and BioTechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Sophie Chen
- Department of Research & Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey, United Kingdom
| | | | - Hiromasa Fujii
- Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Gunjan Guha
- School of Chemical and BioTechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | | | - William G Helferich
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Xujuan Yang
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL, United States
| | - Kanya Honoki
- Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | | | - Satya Prakash
- School of Pharmacy, University College Cork, Cork, Ireland
| | - Sarallah Rezazadeh
- Department of Biology, University of Rochester, Rochester, United States
| | - Rodney E Shackelford
- Department of Pathology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Phuoc T Tran
- Departments of Radiation Oncology & Molecular Radiation Sciences, Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Eddy S Yang
- Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United States
| | - Christopher A Maxwell
- Department of Pediatrics, University of British Columbia, Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Vancouver, Canada.
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EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression. Genes (Basel) 2015; 6:185-205. [PMID: 25836926 PMCID: PMC4488660 DOI: 10.3390/genes6020185] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 03/19/2015] [Accepted: 03/23/2015] [Indexed: 12/12/2022] Open
Abstract
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.
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Fleet JC. Animal models of gastrointestinal and liver diseases. New mouse models for studying dietary prevention of colorectal cancer. Am J Physiol Gastrointest Liver Physiol 2014; 307:G249-59. [PMID: 24875098 PMCID: PMC4121636 DOI: 10.1152/ajpgi.00019.2014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a heterogeneous disease that is one of the major causes of cancer death in the U.S. There is evidence that lifestyle factors like diet can modulate the course of this disease. Demonstrating the benefit and mechanism of action of dietary interventions against colon cancer will require studies in preclinical models. Many mouse models have been developed to study colon cancer but no single model can reflect all types of colon cancer in terms of molecular etiology. In addition, many models develop only low-grade cancers and are confounded by development of the disease outside of the colon. This review will discuss how mice can be used to model human colon cancer and it will describe a variety of new mouse models that develop colon-restricted cancer as well as more advanced phenotypes for studies of late-state disease.
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Affiliation(s)
- James C. Fleet
- 1Department of Nutrition Science, Purdue University, West Lafayette, Indiana; and ,2Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana
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