LAUSR

Key Points Questions What is the incidence rate of germline alterations in CDH1, which has been reported as a susceptibility gene present in 25% to 50% of patients with hereditary diffuse gastric cancer (HDGC), and is there a genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC? Findings In this cohort study of 284 Chinese patients with HDGC, the frequency of CDH1 germline alterations was low (2.8%), and germline alterations, insertions, and deletions were most frequently found in MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO. Double-hit events in genes such as CACNA1D were observed among patients with HDGC. Meaning This study’s findings challenge the previously reported high frequency of CDH1 germline alterations in HDGC and suggest that double-hit events may serve as important mechanisms for HDGC tumorigenesis; the study also provided a genetic landscape and identified new susceptibility genes for HDGC.