Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study

Abstract

BackgroundApproximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese.MethodsWe retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations inBRCA1,BRCA2,ATM,PALB2,BRIP1,CHEK1,CHEK2,FANCAandFANCLwere selected for analysis.Results89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly inATM(30.33%), followed byBRIP1(17.98%),BRCA2(14.61%),BRCA1(12.36%),FANCA(10.11%),PALB2(10.11%),FANCL(6.74%),CHEK1(3.37%) andCHEK2(3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235).ConclusionOur data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.