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Hereditary Gastric Cancer Contributors ID'd Through Retrospective Exome Analysis

In a paper in JAMA Network Open, a team from Sun Yat-Sen University Cancer Center and other centers in China profiles hereditary diffuse gastric cancer (HDGC) risk factors. Starting with data on more than 10,400 gastric cancer cases, the investigators focused in on 542 patients with HDGC. From there, they retrospectively analyzed available exome or targeted sequence data for 284 Chinese individuals with HDGC, searching for germline contributors to the condition, including known risk variants in CDH1. Along with germline risk variants in more than a dozen new and known risk genes, the authors brought in corresponding tumor sequence data for 186 of the cases, uncovering somatic CDH1 alterations in more than one-quarter of the cases, while highlighting a somatic mutation signature linked to a fungal toxin called aflatoxin. "This cohort study provides a genetic landscape for HDGC that challenges the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes," they write. "Analyses of variant signatures and double-hit events revealed important mechanisms for HDGC tumorigenesis."