Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer mortality. Three hereditary gastric cancer syndromes have been described; hereditary diffuse gastric cancer (HDGC), familial intestinal gastric cancer (FIGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Thirty per cent of HDGC families have heterozygous germline mutations in CDH1, which encodes E-cadherin. A germline truncating mutation in the gene encoding α-E-catenin (CTNNA1) was also recently discovered in a family with HDGC, but no other genes specifically predisposing to gastric cancer have been identified, leaving the majority of cases showing familial aggregation without a known genetic cause. The aim of this study was to find the putative gastric cancer predisposing gene defect in a family with HDGC that had previously been tested negative for mutations in CDH1. In this family, there were six cases of diffuse gastric cancer in two generations. Exome sequencing was applied to two affected family members. The shared variants which were predicted deleterious in silico and could not be found in databases or in a control set of over 4,000 individuals were Sanger sequenced in a third family member. Three candidate variants were identified: p.Glu1313Lys in Insulin receptor (INSR), p.Arg81Pro in F-box protein 24 (FBXO24) and p.Pro1146Leu in DOT1-like histone H3K79 methyltransferase (DOT1L). These variants and adjacent regions were screened for in an additional 26 gastric cancer patients with a confirmed (n = 13) or suspected (n = 13) family history of disease, but no other non-synonymous mutations were identified. This study identifies INSR, FBXO24 and DOT1L as new candidate diffuse gastric cancer susceptibility genes, which should be validated in other populations. Of these genes, INSR is of special interest as insulin signaling was recently shown to affect tumor cell invasion capability by modulating E-cadherin glycosylation.