Pathogenic germline variants in mismatch repair genes in patients with microsatellite instability-high gastric cancer
Abstract
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…
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