| Summary: | Importance. Familial aggregation occurs in approximately 10% of gastric cancers, which are generally sub-classified histologically as intestinal-type and diffuse gastric cancers. Though the genetic basis of familial intestinal-type gastric cancers is not known, in <50% of families clinically defined as hereditary diffuse gastric cancer, germline mutations in the E-cadherin gene, CDH1, are detected. This has lead to management guidelines and prevention strategies for mutation carriers. Objectives. To determine whether pathogenic germline mutations in genes alternative to CDH1 can be found in hereditary gastric cancer families using a multiplex panel sequencing approach. Design, Setting and Participants. One hundred fifteen probands from families who met the International Gastric Cancer Linkage Consortium clinical criteria for hereditary diffuse gastric cancer (n=106) or familial intestinal-type gastric cancer (n=9) were included. All diffuse gastric cancer probands tested negative for CDH1-mutations. Germline DNA was screened against a custom panel of 55 genes, including 14 prospective gastric cancer susceptibility genes, using a multiplexed amplicon-based next generation sequencing assay. Candidate mutations were validated via Sanger sequencing. Tumours from pathogenic mutation-positive probands were evaluated by immunohistochemistry. Results. Of 115 probands, four clearly pathogenic truncating mutations were identified in unrelated families, including two different mutations in CTNNA1 (alpha-catenin) and two different mutations in BRCA2. Previously described, functionally pathogenic missense mutations in SDHB (2 families) and STK11 (2 families) were also seen. Additional truncating mutations of likely lower penetrance were identified in ATM (4 families), MSR1 (2 families) and PALB2 (1 family). Cancers from carriers of CTNNA1 truncating variants had prominent loss of protein expression, further supporting their pathogenicity. Conclusion and Relevance. Using a multi-gene panel, families with hereditary gastric cancer were found to carry pathogenic mutations in genes commonly associated with other cancer susceptibility syndromes. In addition, this data suggests that familial gastric cancers, specifically hereditary diffuse gastric cancer syndrome, may benefit from a genetic, rather than clinical, classification. The genetic basis of the remaining families is likely attributable to mutations in genes yet to be implicated in hereditary gastric cancer or, in the diffuse gastric cancer families, atypical aberrations in the non-coding regions of CDH1. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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