Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer

Abstract

ImportanceThe E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown.ObjectiveTo assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC.Design, Setting, and ParticipantsThis cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020.Main Outcomes and MeasuresIncidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC.ResultsAmong 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC.Conclusions and RelevanceThis study provided a genetic landscape for HDGC. The study’s findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

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“…38-44 NCKAP5 , potentially functioning in microtubule bundle formation and microtubule depolymerization, is less studied, and polymorphisms in this gene are reported to be associated with the clinical outcome of gastric cancer patients in a recent study. 45 Overall, our study suggests different genetic factors controlling tumor onset, multiplicity, metastasis, as well as the site of metastasis.…”

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“…Germline variants have been found in the MSR1 gene and have been associated with susceptibility to hereditary prostate cancer 26 – 28 and in patients with upper gastrointestinal pathologies such as Barrett’s esophagus and esophageal adenocarcinoma 24 . Germline variants of MSR1 have also been identified rarely in cases of hereditary diffuse gastric cancer 29 and have shown function in M2 macrophage polarization, with emerging functions being seen in tumor-associated macrophages 30 , 31 . Three isoforms exist via alternative splicing of this gene, with isoforms 1 and 2 acting as functional receptors and able to modulate endocytosis of modified low-density lipoproteins (m-LDL) 32 , and isoform 3, a truncated isoform, unable to internalize m-LDL and interestingly capable of acting in a dominant negative fashion when co-expressed with isoforms 1 and 2 31 , 32 .…”

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“…Literature reports suggest that 30% to 50% of HDGC patients have truncating mutations in CDH1 [ 294 ]. Exome and targeted sequencing results from 284 clinical HDGC patients’ leukocyte samples and paired 186 tumor samples in China showed that the germline mutation rate of CDH1 was only 2.8% [ 295 ], indicating that the genetic susceptibility to HDGC in China may differ from Western countries. Carriers of CDH1 gene mutations have a cumulative risk of developing gastric cancer by the age of 80, estimated at approximately 67% for males and 83% for females.…”