Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature

Zhang, Li; Bhaskaran, Shanmuga Priya; Huang, Teng; Dong, Hongyan; Chandratre, Khyati; Wu, Xiaobing; Qin, Zixin; Wang, Xiaoyu; Cao, Wen; Chen, Tianhui; Lynch, Henry T.; Wang, San Ming

doi:10.1016/j.ejca.2019.11.004

Cited by 13 publications

(17 citation statements)

References 41 publications

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“…All the pathogenic variants identified in Taiwanese population are present in public BRCA databases. Similar situation exists for the pathogenic variants identified in other Asian populations (Bhaskaran et al, 2019;Bhaskaran et al, 2020;Dong et al, 2020;Qin et al, 2020;Zhang et al, 2020). In the meantime, 44.1% of the BRCA variants identified in Taiwanese population remain as novel, VUS, and unclassified variants.…”

Section: Discussionmentioning

confidence: 54%

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Chian¹,

Sinha²,

Qin³

et al. 2021

Front. Mol. Biosci.

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BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan’s subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique model to study human BRCA variation. Through collecting, standardizing, annotating, and classifying publicly available BRCA variants derived from Taiwanese general population and the cancer cohort, we identified 335 BRCA variants, of which 164 were from 1,517 non-cancer individuals, 126 from 2,665 cancer individuals, and 45 from both types of individuals. We compared the variant data with those from other ethnic populations such as mainland Chinese, Macau Chinese, Japanese, Korean, Indian, and non-Asians. We observed that the sharing rates with other Asian ethnic populations were correlated with its genetic relationship. Over 60% of the 335 Taiwanese BRCA variants were VUS, unclassified variants, or novel variants, reflecting the ethnic-specific features of Taiwanese BRCA variation. While it remains challenging to classify these variants, our structural and in silico analyses predicted their enrichment of BRCA deleterious variants. We further determined the 3.8% prevalence of BRCA pathogenic variants in the Taiwanese breast cancer cohort, and determined 0.53% prevalence of the BRCA pathogenic variants in Taiwanese general population, with the estimated 126,140 BRCA pathogenic variant carriers. We identified BRCA2 c.5164_5165delAG at BRCA2 BRC6 motif as a potential founder mutation in Taiwanese population. Our study on BRCA variation in Taiwanese and other East Asian populations demonstrates that ethnic specificity is a common phenomenon for BRCA variation in East Asian population; the data generated from the study provide a reference for clinical applications in BRCA-related cancer in Taiwanese population.

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Section: Discussionmentioning

confidence: 54%

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Chian¹,

Sinha²,

Qin³

et al. 2021

Front. Mol. Biosci.

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“…LGRs in MMR genes in China, a finding that has often been missed by previous next-generation sequencing (22,31). In the current study, we systematically investigated the diverse mutation patterns of MSH2 and the clinicopathological characteristics of patients with MSH2 abnormalities in our cohort, especially LGRs, and the corresponding specific genotype-phenotype associations.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic MSH2 Related to Genomic Deletions in the MSH2/EPCAM Genes in Colorectal Cancer Patients With Suspected Lynch Syndrome

et al. 2021

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BackgroundA large proportion of patients with Lynch syndrome (LS) have MSH2 abnormalities, but genotype-phenotype studies of MSH2 mutations in LS are still lacking. The aim of this study was to comprehensively analyze the clinicopathological characteristics and molecular basis of colorectal cancer (CRC) in patients with uncommon MSH2 cytoplasmic expression.MethodsWe retrospectively reviewed 4195 consecutive cases of CRC patients diagnosed between January 2015 and December 2017 at the Cancer Hospital Chinese Academy of Medical Sciences. Of the 4195 patients with CRC, 69 were indicated to have abnormal MSH2 expression through tumor immunohistochemical staining. Genetic tests, such as next-generation sequencing, large genomic rearrangement (LGR) analysis, microsatellite instability status analysis and genomic breakpoint analysis, were performed. Clinicopathological and molecular characteristics and clinical immunotherapy response were analyzed.ResultsForty-five of 69 patients were identified to have LS with pathogenic germline mutations in MSH2 and/or EPCAM. Of these LS patients, 26.7% were confirmed to harbor large genomic rearrangements (LGRs). Of note, three tumors from two unrelated family pedigrees exhibited a rare cytoplasmic MSH2 staining pattern that was found in LS patients with EPCAM/MSH2 deletions. RNA analysis showed that two novel mRNA fusions of EPCAM and MSH2 resulted in the predicted protein fusion with MSH2 cytoplasmic localization. Analyses of genomic breakpoints indicated that two novel deletions of EPCAM and MSH2 originated from Alu repeat-mediated recombination events. Our study also provides clinical evidence for the beneficial effect of the PD-1 inhibitor pembrolizumab for CRC patients that exhibit cytoplasmic MSH2 staining.ConclusionOur study demonstrates that the rare cytoplasmic MSH2 staining pattern should be fully recognized by pathologists and geneticists. Given the specific genotype-phenotype correlation in LS screening, we advocate that all CRC patients with cytoplasmic MSH2 staining in histology should be screened for LGRs of EPCAM and MSH2.

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“…MLH1 and MSH2 are the most common germline mutations reported by clinical research, accounting for about 90 % of all MMR gene mutations [15]. 11 MLH1 variants, such as c.1588_1590delTTC, c.1163_1164insT and c.265G > T, and 18 MSH2 variants, such as c.943-1G > A and c.595T > C were the high-frequency MMR variants in China [1]. In neighboring Korea and Japan, MLH1 and MSH2 was also the most common germline mutation [9,16].…”

Section: Ls-related Cancers and Mmr Mutations In Chinamentioning

confidence: 99%

“…DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt their mismatch repair function, cause genome instability and lead to increased cancer risk in the mutation carriers as represented by Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer (HNPCC) [1]. MMR genes, such as mutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6) and postmeiotic segregation increased 2 (PMS2), express MMR proteins, which are nucleic acid hydrolases that hydrolyze mismatched bases in the process of DNA replication to make DNA replication accurate.…”

Section: Introductionmentioning

confidence: 99%

“…A largescale comprehensive screening found that 540 MMR variants were identified in the Chinese population, and the pathogenic/likely pathogenic carrier rate was 1.6 %. More than 90 % of the variants only existed in Chinese ethnicity, showing an ethnic-specific nature [1]. In 2019, a new MLH1 c.1896 + 5G > A germline mutation was found in the Chinese LS-related lung and gastric cancer [2].…”

Section: Introductionmentioning

confidence: 99%

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Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

Zhang

Chen

2021

Hered Cancer Clin Pract

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DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.

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Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature

Cited by 13 publications

References 41 publications

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Cytoplasmic MSH2 Related to Genomic Deletions in the MSH2/EPCAM Genes in Colorectal Cancer Patients With Suspected Lynch Syndrome

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

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