Hereditary diffuse gastric cancer (HDGC) is closely related to germline mutation of CDH1. In addition, potential pathogenic germline variants in other candidate genes were detected in FGC and HDGC families. However, comprehensive genetic profile of HDGC predisposing gene variants in Chinese Familial gastric cancer (FGC) and HDGC patients are yet to be elucidated.
We collected peripheral blood from 28 early-onset DGC patients and from a first degree relative DGC patient who was diagnosed at age of 50. All 29 patients fulfilled IGCLC 2015 criteria for HDGC clinical diagnosis and genetic testing. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastric ancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and corresponding functional impact was predicted by in silico tools.
Among previously reported gastric cancer susceptibility genes, CDH1, BRCA2, MAP3K6 expressed the most predisposing SNV and Indel candidates. In addition, a novel splice-site variant, c.2165-1G>A, in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Moreover, BCR gene exhibited as the most prevalent gastric cancer predisposing gene with filtered variants primarily enriched in RhoGAP domain. Pathway enrichment analysis showed that the top three predisposing variant candidates were enriched in the following signalling pathway: ECM-receptor interaction (P-Value: 0.001), focal adhesion (P-Value: 0.02) and protein digestion and absorption (P-Value: 0.002).
This study suggested that CDH1, BRCA2, MAP3K6 may act as potential gastric cancer susceptibility genes in Chinese early-onset HDGC patients. Further study may be required to investigate the functional role of BCR abnormality, especially in its RhoGAP domain, in the tumorigenesis of gastric cancer. Moreover, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider genes involved in three signalling pathways: ECM-receptor interaction, focal adhesion and protein digestion and absorption.
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Legal entity responsible for the study
Peking University Cancer Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.