Genomic analyses identify 15 susceptibility loci and revealHDAC2,SOX2-OT, andIGF2BP2in a naturally-occurring canine model of gastric cancer

Abstract

Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for theEPAS1(HIF2A) andPTENgenes and a coding variant inCD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois atSOX2-OTandIGF2BP2. Among Tervuren and Sheepdogs,HDAC2putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such asPDZRN3, that have not been associated with human GC.