Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Abstract BackgroundDiffuse gastric cancer (DGC) is known as gastric cancer with diffuse type morphology. Early onset DGC is an indicator of suspicious hereditary diffuse gastric cancer (HDGC). HDGC patient are often less sensitive to chemotherapy and suffer from highly invasive late stage malignancy with poor prognosis. Such hereditary cancer syndrome is closely related to deleterious CDH1 germline variant. In addition, potential pathogenic germline variants in other candidate genes were also observed in HDGC families. However, the profile of gastric cancer (GC) susceptibility gene in Chinese HDGC patients is yet to be elucidated.MethodsTo investigate gastric cancer susceptibility genes in Chinese gastric cancer patients, we collected peripheral blood samples from 29 patients fulfilled both HDGC clinical diagnosis and genetic testing criteria updated on 2015 by IGCLC. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastric cancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and pathogenic variant filtering process was performed to identify potential gastric cancer predisposing variant candidates. Immunohistochemistry was conducted on biopsies from patient who carries potential pathogenic CDH1 germline variant.ResultsIn general, 336296 germline non-synonymous variants were detected from 29 GC patients. According to the pathogenic variant filtering process, 25 germline variant candidates in 22 genes were identified as gastric cancer predisposing variant candidates. In addition, a novel splice-site variant, c.2165-1G>A (NM_004360.4), in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Furthermore, IHC analysis on the ovarian cancer tissue from this patient demonstrated weakly to moderate staining of E-cadherin compared with positive control. Moreover, another two variants, CTNNA1 c.1975_1976del (NM_001903.2), APC c.-19+1G>A (NM_001127511.2), were suspicious of gastric cancer predisposing variants.ConclusionsThis study suggested that CDH1 c.2165-1G>A may act as a gastric cancer predisposing variant. In addition, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider 22 genes observed in this study. Furthermore, the inconclusive results in this study warrant future investigation on gastric cancer susceptibility gene discovery that cohort selection may require more stringent conditions.