Jong Hyuk Yun, Geum Jong Song, In Cho, Sangchul Yun, Myoung Won Son, Sang Hyun Kim, Moon-Soo Lee, Yoon Young Choi
{"title":"微卫星不稳定性高胃癌患者错配修复基因的致病种系变异。","authors":"Jong Hyuk Yun, Geum Jong Song, In Cho, Sangchul Yun, Myoung Won Son, Sang Hyun Kim, Moon-Soo Lee, Yoon Young Choi","doi":"10.21147/j.issn.1000-9604.2025.02.04","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Lynch syndrome (LS) increases the risk of various cancers, including colorectal cancer, endometrial cancer and gastric cancer (GC). The incidence of LS among microsatellite instability-high (MSI-H) GC and their association in South Korea remains underexplored. This study investigates LS-associated pathogenic germline variants in MSI-H GC patients using whole-exome sequencing (WES) on normal tissues.</p><p><strong>Methods: </strong>This retrospective study included patients who underwent gastrectomy for GC at Soonchunhyang University Bucheon and Cheonan Hospitals from January 2011 to October 2023. Among 1,537 patients screened for MSI status, 127 (8.3%) were identified as MSI-H. WES was performed on normal tissues from 123 patients. Pathogenic/likely pathogenic (P/LP) variants in mismatch repair (MMR) genes were identified using <i>in silico</i> models and protein loss assessments in corresponding tumor tissues.</p><p><strong>Results: </strong>Of the 127 MSI-H GC cases, characteristics aligned with typical MSI-H GC. The average age was 70.02 years, with 98 (77.2%) located in the lower body and 81 (63.8%) of the intestinal type. All five MSI markers were positive in 46.5% of cases, whereas four markers were positive in 27.6%. Of the MSI-H GCs, 10 LS candidates were identified. Three patients had known P/LP variants [<i>MLH1</i> (c.1758dup), <i>MSH6</i> (c.3261dup), <i>MSH2</i> (c.1241T>C)]. Seven patients had variants of unknown significance (VUS) in MMR genes. Six (4.9%) patients were identified as having LS or possible LS, including one patient with the MLH1 (c.1153C>T) variant previously classified as VUS but now considered LS-associated.</p><p><strong>Conclusions: </strong>This large-scale screening for LS in MSI-H GC patients using retrospective samples confirmed the lower incidence of LS than those of colorectal or endometrial cancer and GC patients in Western countries, emphasizing the need for clinical consideration in managing MSI-H GC patients.</p>","PeriodicalId":9882,"journal":{"name":"Chinese Journal of Cancer Research","volume":"37 2","pages":"165-173"},"PeriodicalIF":7.0000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062985/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pathogenic germline variants in mismatch repair genes in patients with microsatellite instability-high gastric cancer.\",\"authors\":\"Jong Hyuk Yun, Geum Jong Song, In Cho, Sangchul Yun, Myoung Won Son, Sang Hyun Kim, Moon-Soo Lee, Yoon Young Choi\",\"doi\":\"10.21147/j.issn.1000-9604.2025.02.04\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Lynch syndrome (LS) increases the risk of various cancers, including colorectal cancer, endometrial cancer and gastric cancer (GC). The incidence of LS among microsatellite instability-high (MSI-H) GC and their association in South Korea remains underexplored. This study investigates LS-associated pathogenic germline variants in MSI-H GC patients using whole-exome sequencing (WES) on normal tissues.</p><p><strong>Methods: </strong>This retrospective study included patients who underwent gastrectomy for GC at Soonchunhyang University Bucheon and Cheonan Hospitals from January 2011 to October 2023. Among 1,537 patients screened for MSI status, 127 (8.3%) were identified as MSI-H. WES was performed on normal tissues from 123 patients. Pathogenic/likely pathogenic (P/LP) variants in mismatch repair (MMR) genes were identified using <i>in silico</i> models and protein loss assessments in corresponding tumor tissues.</p><p><strong>Results: </strong>Of the 127 MSI-H GC cases, characteristics aligned with typical MSI-H GC. The average age was 70.02 years, with 98 (77.2%) located in the lower body and 81 (63.8%) of the intestinal type. All five MSI markers were positive in 46.5% of cases, whereas four markers were positive in 27.6%. Of the MSI-H GCs, 10 LS candidates were identified. Three patients had known P/LP variants [<i>MLH1</i> (c.1758dup), <i>MSH6</i> (c.3261dup), <i>MSH2</i> (c.1241T>C)]. Seven patients had variants of unknown significance (VUS) in MMR genes. Six (4.9%) patients were identified as having LS or possible LS, including one patient with the MLH1 (c.1153C>T) variant previously classified as VUS but now considered LS-associated.</p><p><strong>Conclusions: </strong>This large-scale screening for LS in MSI-H GC patients using retrospective samples confirmed the lower incidence of LS than those of colorectal or endometrial cancer and GC patients in Western countries, emphasizing the need for clinical consideration in managing MSI-H GC patients.</p>\",\"PeriodicalId\":9882,\"journal\":{\"name\":\"Chinese Journal of Cancer Research\",\"volume\":\"37 2\",\"pages\":\"165-173\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2025-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062985/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chinese Journal of Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.21147/j.issn.1000-9604.2025.02.04\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chinese Journal of Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21147/j.issn.1000-9604.2025.02.04","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Pathogenic germline variants in mismatch repair genes in patients with microsatellite instability-high gastric cancer.
Objective: Lynch syndrome (LS) increases the risk of various cancers, including colorectal cancer, endometrial cancer and gastric cancer (GC). The incidence of LS among microsatellite instability-high (MSI-H) GC and their association in South Korea remains underexplored. This study investigates LS-associated pathogenic germline variants in MSI-H GC patients using whole-exome sequencing (WES) on normal tissues.
Methods: This retrospective study included patients who underwent gastrectomy for GC at Soonchunhyang University Bucheon and Cheonan Hospitals from January 2011 to October 2023. Among 1,537 patients screened for MSI status, 127 (8.3%) were identified as MSI-H. WES was performed on normal tissues from 123 patients. Pathogenic/likely pathogenic (P/LP) variants in mismatch repair (MMR) genes were identified using in silico models and protein loss assessments in corresponding tumor tissues.
Results: Of the 127 MSI-H GC cases, characteristics aligned with typical MSI-H GC. The average age was 70.02 years, with 98 (77.2%) located in the lower body and 81 (63.8%) of the intestinal type. All five MSI markers were positive in 46.5% of cases, whereas four markers were positive in 27.6%. Of the MSI-H GCs, 10 LS candidates were identified. Three patients had known P/LP variants [MLH1 (c.1758dup), MSH6 (c.3261dup), MSH2 (c.1241T>C)]. Seven patients had variants of unknown significance (VUS) in MMR genes. Six (4.9%) patients were identified as having LS or possible LS, including one patient with the MLH1 (c.1153C>T) variant previously classified as VUS but now considered LS-associated.
Conclusions: This large-scale screening for LS in MSI-H GC patients using retrospective samples confirmed the lower incidence of LS than those of colorectal or endometrial cancer and GC patients in Western countries, emphasizing the need for clinical consideration in managing MSI-H GC patients.
期刊介绍:
Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013.
CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.