Gene Summary

Gene:MSH2; mutS homolog 2
Summary:This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA mismatch repair protein Msh2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MSH2 (cancer-related)

Albero-González R, Hernández-Llodrà S, Juanpere N, et al.
Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status.
Virchows Arch. 2019; 475(2):223-231 [PubMed] Related Publications
The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.

Kawashima Y, Nishikawa S, Ninomiya H, et al.
Lung Adenocarcinoma with Lynch Syndrome and the Response to Nivolumab.
Intern Med. 2019; 58(10):1479-1484 [PubMed] Free Access to Full Article Related Publications
Lynch syndrome is caused by mutations in mismatch repair genes that lead to microsatellite instability (MSI). An increased number of mutation-associated neoantigens have been observed in patients with high-frequency MSI (MSI-H) cancer; in addition, membranous programmed death ligand-1 (PD-L1) tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. MSI-H cancer patients are therefore considered to be susceptible to immune checkpoint blockade. We herein report for the first time a case of lung adenocarcinoma with Lynch syndrome and the response to nivolumab.

Toss A, Molinaro E, Sammarini M, et al.
Hereditary ovarian cancers: state of the art.
Minerva Med. 2019; 110(4):301-319 [PubMed] Related Publications
The identification of a mutation in ovarian cancer (OC) predisposition genes plays a crucial role in the management of cancer prevention, diagnosis, and treatment. In healthy carriers, the detection of a specific mutation might justify more intensive and personalised surveillance programmes, chemopreventive measures, and prophylactic surgeries. Moreover, the identification of a mutation in affected OC patients might provide fundamental knowledge of the tumour pathogenesis, thus guiding treatment choices. This is a comprehensive review of the molecular pathways involved in the pathogenesis of hereditary ovarian cancers, the clinical-pathological features of these tumours, and the potential implications for their prevention and clinical management.

Foretová L
Hereditary cancer syndromes, their testing and prevention.
Cas Lek Cesk. 2019; 158(1):15-21 [PubMed] Related Publications
About 5-10 % of cancer diseases may be caused by genetic predisposition, in ovarian cancer it could be almost 20 % of cases. The cause is mostly a pathogenic germline mutation in tumor suppressor genes, DNA repair genes, less frequently in oncogenes. So far, we know more than 200 hereditary cancer syndromes. The most frequently tested are hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), quite frequent are also hereditary gastrointestinal polyposes. Genetic counseling and testing are routinely available for patients or their relatives. Testing methods are changing; nowadays we use next generation sequencing methods (massive parallel sequencing) with testing of panels of high-risk genes. If the mutation is discovered, we may offer the testing to relatives. Genetic testing is indicated by medical geneticist after the genetic counseling session. High-risk individuals should be followed oncology clinics or by other specialists.

Bouvet D, Bodo S, Munier A, et al.
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.
Gastroenterology. 2019; 157(2):421-431 [PubMed] Related Publications
BACKGROUND & AIMS: Approximately 75% of patients with suspected Lynch syndrome carry variants in MLH1 or MSH2, proteins encoded by these genes are required for DNA mismatch repair (MMR). However, 30% of these are variants of unknown significance (VUS). A assay that measures cell response to the cytotoxic effects of a methylating agent can determine the effects of VUS in MMR genes and identify patients with constitutional MMR-deficiency syndrome. We adapted this method to test the effects of VUS in MLH1 and MSH2 genes found in patients with suspected Lynch syndrome.
METHODS: We transiently expressed MLH1 or MSH2 variants in MLH1- or MSH2-null human colorectal cancer cell lines (HCT116 or LoVo), respectively. The MMR process causes death of cells with methylation-damaged DNA bases, so we measured proportions of cells that undergo death following exposure to the methylating agent; cells that escaped its toxicity were considered to have variants that affect function of the gene product. Using this assay, we analyzed 88 variants (mainly missense variants), comprising a validation set of 40 previously classified variants (19 in MLH1 and 21 in MSH2) and a prospective set of 48 VUS (25 in MLH1 and 23 in MSH2). Prediction scores were calculated for all VUS according to the recommendations of the American College of Medical Genetics and Genomics, based on clinical, somatic, in silico, population, and functional data.
RESULTS: The assay correctly classified 39 of 40 variants in the validation set. The assay identified 12 VUS that did alter function of the gene product and 28 VUS that did not; the remaining 8 VUS had intermediate effects on MMR capacity and could not be classified. Comparison of assay results with prediction scores confirmed the ability of the assay to discriminate VUS that affected the function of the gene products from those that did not.
CONCLUSIONS: Using an assay that measures the ability of the cells to undergo death following DNA damage induction by a methylating agent, we were able to assess whether variants in MLH1 and MSH2 cause defects in DNA MMR. This assay might be used to help assessing the pathogenicity of VUS in MLH1 and MSH2 found in patients with suspected Lynch syndrome.

Liu Y, Wang M, Chen Q, et al.
A novel heterozygous large deletion of MSH6 gene in a Chinese family with Lynch syndrome.
Gene. 2019; 704:103-112 [PubMed] Related Publications
Lynch syndrome (LS) is a common cancer syndrome that is inherited in an autosomal dominant manner. Its pathogenesis is thought to be closely related to germline mutations of mismatch repair (MMR) genes such as the MLH1, MSH2, PMS2 and MSH6 genes. This study identifies a Chinese family with LS clinically diagnosed according to the Amsterdam II criteria. In these patients, immuno-histochemical staining showed negative MSH6 expressions but positive MLH1, MSH2, and PMS2 expressions. In order to further explore the molecular biology of this LS family, we used targeted next-generation sequencing (NGS) and Multiplex ligation dependent probe amplification (MLPA) to identify the mutation and verify the authenticity of the mutation in 15 family members. For NGS, two panels have been used, one is of MLH1, MSH2, PMS2 and MSH6 genes, the other one is of 139 cancer genetic susceptibility genes. And for the large deletions/duplications can also be identified by NGS panel, an adjusted data analysis strategy of NGS has been used. As a result, we identified a novel heterozygous large deletion in MSH6 gene that was found to be co-segregated among affected family members. This deletion results in the loss of a 3246 bp-sized fragment in MSH6 gene exons 5-9 which represents the coding regions of the MSH6 ATPase domain. This novel mutation has yet to be documented in the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database. This mutation resulted in MSH6 protein losing gene mismatch repair function, and further caused the microsatellite instable. We speculate that this mutation may significantly impact MMR function through impaired ATP domain function. Theoretically, this proband would likely benefit from PD-1 immune check-point blockade therapy, but conversely, we observed that tumors appeared to rapidly progress after 4 sessions of anti-PD-1 treatment. Further studies to validate the effectiveness of anti-PD-1 treatments in carriers of this mutation are necessary.

Germini DE, Franco MIF, Fonseca FLA, et al.
Association of expression of inflammatory response genes and DNA repair genes in colorectal carcinoma.
Tumour Biol. 2019; 42(4):1010428319843042 [PubMed] Related Publications
Inflammation is an important etiological factor of colorectal carcinoma and may be related to colorectal carcinoma growth and proliferation. This study aimed to verify whether the presence of chronic inflammation represented by tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 gene expression is related to hMLH1, hMSH2, hMSH6, and PMS2 gene expression and the corresponding protein levels of these genes from the DNA repair system. A total of 83 patients were operated on for curative or palliative colorectal carcinoma. Expression of the inflammatory response genes tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 as well as expression of the hMLH1, hMSH2, hMSH6, and PMS2 genes of the DNA repair system (mismatch repair) and the expression levels of the corresponding mismatch repair proteins were measured in neoplastic tissue by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Associations were observed between hMSH6 mRNA expression and interleukin-2 mRNA expression (p = 0.026) as well as between hMLH1 and hMSH2 gene expression and tumor necrosis factor-α gene expression (p = 0.042). Higher tissue levels of interleukin-2 and tumor necrosis factor-α gene expression were associated with lower hMSH6, hMLH1, and hMSH2 gene expression.

Cini G, Quaia M, Canzonieri V, et al.
Toward a better definition of EPCAM deletions in Lynch Syndrome: Report of new variants in Italy and the associated molecular phenotype.
Mol Genet Genomic Med. 2019; 7(5):e587 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination.
METHODS: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS).
RESULTS: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae.
CONCLUSION: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.

Ito T, Yamaguchi T, Wakatsuki T, et al.
The single-base-pair deletion, MSH2 c.2635-3delC affecting intron 15 splicing can be a cause of Lynch syndrome.
Jpn J Clin Oncol. 2019; 49(5):477-480 [PubMed] Related Publications
The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.

Hajirawala L, Barton JS
Diagnosis and Management of Lynch Syndrome.
Dis Colon Rectum. 2019; 62(4):403-405 [PubMed] Related Publications
CASE SUMMARY: A 56-year-old man with a history of hypertension and hyperlipidemia was referred by gastroenterology for bleeding per rectum. Because of a family history of colon cancer, he had several prior colonoscopies, most recently 3 years ago, without evidence of pathology. His mother was diagnosed with colon cancer in her mid-40s. His current colonoscopy demonstrated a 2.4 × 1.5 cm cecal adenocarcinoma. Staging workup revealed no evidence of metastatic disease. Because of the patient's family history, the specimen was further evaluated and found to have high microsatellite instability (MSI-H). The patient was referred to a genetic counselor and found to have a germline pathogenic variant in MSH6 on gene panel testing. The patient did not have a family history of any extracolonic malignancies.The patient underwent an uncomplicated laparoscopic total abdominal colectomy with ileorectal anastomosis, which revealed a T2N0Mx adenocarcinoma with abundant peritumoral lymphocytes. He was discharged on postoperative day 2, and recuperated appropriately from surgery. Follow-up surveillance proctoscopy showed no evidence of disease. His sole offspring, a 25-year-old man, was negative for a pathogenic variant in MSH6 and had no polyps on colonoscopy. His siblings did demonstrate a pathogenic variant in MSH6 and are currently opting for annual surveillance colonoscopy.

Pandey AS, Shrestha S
A novel frameshift mutation in the
Indian J Cancer. 2018 Oct-Dec; 55(4):410-412 [PubMed] Related Publications
A novel mutation in the MLH1 gene likely to be pathogenic for Lynch syndrome was discovered in a proband with a family history of colon cancer. Immunohistochemistry showed negative expression of PMS2 and MLH1 in the resected tumor sample. The mutation lies at the highly conserved C-terminus of the MLH1 protein, the region through which it dimerizes with PMS2 to carry out its mismatch repair function.

Haron NH, Mohamad Hanif EA, Abdul Manaf MR, et al.
Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer
Asian Pac J Cancer Prev. 2019; 20(2):509-517 [PubMed] Related Publications
Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method: A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.

Barrett R, Neben CL, Zimmer AD, et al.
A scalable, aggregated genotypic-phenotypic database for human disease variation.
Database (Oxford). 2019; 2019 [PubMed] Free Access to Full Article Related Publications
Next generation sequencing multi-gene panels have greatly improved the diagnostic yield and cost effectiveness of genetic testing and are rapidly being integrated into the clinic for hereditary cancer risk. With this technology comes a dramatic increase in the volume, type and complexity of data. This invaluable data though is too often buried or inaccessible to researchers, especially to those without strong analytical or programming skills. To effectively share comprehensive, integrated genotypic-phenotypic data, we built Color Data, a publicly available, cloud-based database that supports broad access and data literacy. The database is composed of 50 000 individuals who were sequenced for 30 genes associated with hereditary cancer risk and provides useful information on allele frequency and variant classification, as well as associated phenotypic information such as demographics and personal and family history. Our user-friendly interface allows researchers to easily execute their own queries with filtering, and the results of queries can be shared and/or downloaded. The rapid and broad dissemination of these research results will help increase the value of, and reduce the waste in, scientific resources and data. Furthermore, the database is able to quickly scale and support integration of additional genes and human hereditary conditions. We hope that this database will help researchers and scientists explore genotype-phenotype correlations in hereditary cancer, identify novel variants for functional analysis and enable data-driven drug discovery and development.

Cappellesso R, Lo Mele M, Munari G, et al.
Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers.
Pathol Res Pract. 2019; 215(5):957-962 [PubMed] Related Publications
Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.

You YN, Borras E, Chang K, et al.
Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.
Dis Colon Rectum. 2019; 62(4):429-437 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.
OBJECTIVE: The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.
DESIGN: This was a retrospective study.
SETTINGS: The study was conducted at a tertiary-referral institution.
PATIENTS: Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.
INTERVENTIONS: Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.
MAIN OUTCOME MEASURES: We measured detection of pathogenic germline variants.
RESULTS: A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).
LIMITATIONS: This study was limited by its small sample size and advanced-stage patients.
CONCLUSIONS: Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at

Das S, Salami SS, Spratt DE, et al.
Bringing Prostate Cancer Germline Genetics into Clinical Practice.
J Urol. 2019; 202(2):223-230 [PubMed] Related Publications
PURPOSE: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations.
MATERIALS AND METHODS: We searched PubMed® for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer Network®, Bureau of Labor Statistics and National Society of Genetic Counselors websites.
RESULTS: A number of germline mutations in DNA damage repair genes ( BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes ( MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study ( NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors.
CONCLUSIONS: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

Westwood A, Glover A, Hutchins G, et al.
Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation.
J Clin Pathol. 2019; 72(6):443-447 [PubMed] Related Publications
Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/-MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.

Quaas A, Heydt C, Waldschmidt D, et al.
Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma.
BMC Gastroenterol. 2019; 19(1):21 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.
METHODS: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).
RESULTS: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.
CONCLUSION: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Ohmoto A, Yachida S, Morizane C
Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.
Int J Mol Sci. 2019; 20(3) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as

Hirotsu Y, Mochizuki H, Amemiya K, et al.
Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer.
Med Oncol. 2019; 36(3):23 [PubMed] Related Publications
Signet ring cell (SRC) gastric cancer at advanced stage has poor prognosis. While a recent study reported nearly one-third of SRC cases contain tumors with deficient mismatch repair (MMR) genes, other studies in SRC have been inconclusive. To re-analyze the results, we performed immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2 proteins in 38 SRC gastric tumors compared with 109 non-SRC (NSRC) tumors from 94 patients. In contrast to the previous study, all SRC gastric tumors normally expressed MMR proteins, whereas 22 of 109 of NSRC (20%) showed deficient MMR proteins. To reinforce our results, we referred to the Cancer Genome Atlas (TCGA) genomic database and found that only 6 (6%) of 99 samples with diffuse gastric tumors showed deficient MMR, whereas 64 (21%) of 304 in intestinal gastric tumors showed deficient MMR. Our results as well as the TCGA database indicated that MMR genes are infrequently inactivated in SRC gastric cancer. These findings indicate that SRC patients may not be the best candidates for immuno-oncology therapy.

Roncati L
Microsatellite Instability Predicts Response to Anti-PD1 Immunotherapy in Metastatic Melanoma.
Acta Dermatovenerol Croat. 2018; 26(4):341-343 [PubMed] Related Publications
Dear Editor, Immune-checkpoint blockade is a type of passive immunotherapy aimed at enhancing preexisting anti-tumor responses of the organism, blocking self-tolerance molecular interactions between T-lymphocytes and neoplastic cells (1,2). Despite a significant increase in progression-free survival, a large proportion of patients affected by metastatic melanoma do not show durable responses even after appropriate diagnostic categorization and shared therapeutic choices (3-9). Therefore, predictive biomarkers of clinical response are urgently needed, and predictive immunohistochemistry (IHC) meets these requirements. Strong evidence suggests that DNA mismatch repair (MMR) deficiency is a frequent condition in malignant melanoma, as well as in other tumors (10). As is known, DNA MMR is a safeguard system for the detection and repair of DNA errors, which can randomly occur in the phase of DNA replication inside the cell. In humans, seven DNA MMR proteins (Mlh1, Mlh3, Msh2, Msh3, Msh6, Pms1, and Pms2) work in a coordinated and sequential manner to repair DNA mismatches. When this system is defective, the cell accumulates a series of replication errors in terms of new microsatellites; therefore, a condition of genetic hypermutability and microsatellite instability (MSI) takes place inside the cell itself (11). For this reason, my working group has started to search for MMR protein deficiency in melanoma biopsies from patients of both sexes and of all ages with metastatic spread, correlating the data with the response to pembrolizumab, the well-known anti-programmed cell death protein 1 (PD1) human monoclonal immunoglobulin G4, capable of blocking the interaction between PD1, the surface receptor of activated T-lymphocytes, and its ligand, the programmed death-ligand 1 (PD-L1), favoring melanoma cell attack by T-lymphocytes (1) rather than its depression (12). PD-L1 is highly expressed in about half of all melanomas and thus the role of PD1 in melanoma immune evasion is now well established (13). Surprisingly, the best therapeutic results to pembrolizumab, in terms of progression-free survival and overall survival, occur precisely in those patients, approximately 7% in my database, affected by deficient MMR (dMMR) melanomas. In particular, the most important benefits to pembrolizumab-based treatment have occurred in a female patient, who developed a subungual melanoma in the second finger of the left hand at the age of 41 years, together with lymph node metastases to ipsilateral axilla at the onset. The patient was promptly submitted to amputation of the first phalanx and emptying of the axillary cable. The primary tumor was a vertical growth phase melanoma with a Breslow's depth of 1.4 mm; three mitotic figures for 1 mm2 were ascertained. There was no evidence of ulceration, regression, microsatellitosis, or lymphocytic infiltration; moreover, the surgical margins tested free of disease. Further molecular analyses did not show rearrangements in B-RAF and C-KIT genes. After four years, metastases appeared in the brain and ileum; however, at present the patient is still alive and in complete pembrolizumab response with progression-free survival and overall survival of 956 days and 2546 days, respectively. The tumor was afterwards identified as a dMMR melanoma for an exclusive loss of Msh6 expression on IHC (Figure 1). This finding is in line with the fact that the U.S. Food and Drug Administration has approved the use of pembrolizumab in 2017 for unresectable or metastatic solid tumors with MMR deficiency (14). In conclusion, dMMR melanoma seems to be a particular subset of disease that can be identified with high sensibility and specificity by predictive IHC as a complete loss of one or more DNA MMR proteins and that deserves targeted therapy.

Panagopoulou M, Karaglani M, Balgkouranidou I, et al.
Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers.
Oncogene. 2019; 38(18):3387-3401 [PubMed] Related Publications
Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis.

Yu H, Hemminki A, Sundquist K, Hemminki K
Familial Associations of Colon and Rectal Cancers With Other Cancers.
Dis Colon Rectum. 2019; 62(2):189-195 [PubMed] Related Publications
BACKGROUND: Many studies have indicated that colon and rectal cancers differ in etiology and histology.
OBJECTIVE: The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific.
DESIGN: A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer.
SETTINGS: The study was conducted using the Swedish Family-Cancer Database.
MAIN OUTCOME MEASURES: The outcome measure was relative risk.
RESULTS: Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% CI, 1.74-1.90) vs 1.61 (95% CI, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% CI, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant.
LIMITATIONS: Genetic data are unavailable in the database.
CONCLUSIONS: Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition. See Video Abstract at

Lotan TL, Kaur HB, Alharbi AM, et al.
DNA damage repair alterations are frequent in prostatic adenocarcinomas with focal pleomorphic giant-cell features.
Histopathology. 2019; 74(6):836-843 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
AIMS: Prostatic adenocarcinomas with focal pleomorphic giant-cell features constitute a rare tumour subtype with abysmal clinical outcomes. More than one-third of patients with this histology die within a year of the initial diagnosis of prostate cancer. We aimed to perform molecular profiling of these tumors to identify potential therapeutic targets.
METHODS AND RESULTS: Here, we performed next-generation sequencing with a highly validated targeted panel (UW-OncoPlex) on somatic tumour DNA extracted from eight cases of prostatic adenocarcinoma with focal pleomorphic giant-cell features, including cases with and without prior treatment for prostate cancer. We found that DNA damage repair mutations are common in this rare subset of prostate tumours, with two of eight having bi-allelic pathogenic mutations in homologous DNA repair genes (including BRCA2 and NBN) and two of eight having bi-allelic pathogenic mutations in mismatch repair genes (including MSH2 and MLH1).
CONCLUSION: These data are consistent with emerging data showing that DNA repair alterations are enriched among castration-resistant prostate cancer and aggressive subsets of primary tumours. Given that these patients are potential candidates for poly(ADP-ribose) polymerase inhibitor and/or immune checkpoint blockade, and have a poor prognosis with standard therapy, we recommend that tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant-cell features.

Sui QQ, Jiang W, Wu XD, et al.
A frameshift mutation in exon 19 of MLH1 in a Chinese Lynch syndrome family: a pedigree study.
J Zhejiang Univ Sci B. 2019 Jan.; 20(1):105-108 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.

Fulk K, Milam MR, Li S, et al.
Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing.
Gynecol Oncol. 2019; 152(3):612-617 [PubMed] Related Publications
OBJECTIVE: We explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory.
METHODS: The combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression.
RESULTS: Fourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes.
CONCLUSIONS: Women with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.

Mota JM, Sousa LG, Braghiroli MI, et al.
Pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden: Two case reports.
Medicine (Baltimore). 2018; 97(52):e13517 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
RATIONALE: In the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes.
PATIENT CONCERNS: We report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments.
DIAGNOSIS: Next-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation.
INTERVENTIONS: They were treated with pembrolizumab (100 to 200 mg every 3 weeks).
OUTCOMES: The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.
LESSONS: To the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.

Mäki-Nevala S, Valo S, Ristimäki A, et al.
DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression.
EBioMedicine. 2019; 39:280-291 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR.
METHODS: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing.
FINDINGS: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas.
INTERPRETATION: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. FUND: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Juselius Foundation, and HiLIFE.

Keränen A, Ghazi S, Carlson J, et al.
Testing strategies to reduce morbidity and mortality from Lynch syndrome.
Scand J Gastroenterol. 2018; 53(12):1535-1540 [PubMed] Related Publications
OBJECTIVE: Lynch syndrome (LS) has an autosomal dominant inheritance pattern and is associated with increased risk for colorectal cancer (CRC) and other cancers. Various strategies are used to identify patients at risk and offer surveillance and preventive programs, the cost effectiveness of which is much dependent on the prevalence of LS in a population. Universal testing (UT) is proposed as an effective measure, targeting all newly diagnosed CRC patients under a certain age.
MATERIALS AND METHODS: LS cases were identified in a cohort of 572 consecutive CRC patients. Immunohistochemistry was performed in 539 cases, using antibodies against mismatch repair proteins MLH1, PMS2, MSH2, and MSH6. Microsatellite instability and gene mutation screening were performed in 57 cases.
RESULTS: In total 11 pathogenic variants were detected, identifying LS in 1.9% of new CRC cases. Comparing the results with current clinical methods, 2 pathogenic variants were found with Amsterdam criteria and 9 when using either Bethesda guidelines or our institution's prior clinical criteria. Pathogenic variants in MSH6 were the most common in our series. We also found different outcomes using different age cut offs.
CONCLUSION: Our study demonstrates that UT of tumors before age on onset at 75 years would most likely be cost-efficient and essentially equivalent to applying the Bethesda guidelines or our institution's prior clinical criteria on all new CRC.

Ding N, Miller SA, Savant SS, O'Hagan HM
JAK2 regulates mismatch repair protein-mediated epigenetic alterations in response to oxidative damage.
Environ Mol Mutagen. 2019; 60(4):308-319 [PubMed] Related Publications
At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H

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