Data from: Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer

Gastric cancer ranks as the fifth most common human cancer worldwide and
has a poor survival rate and limited treatment options. Despite the high
prevalence and mortality rate, the genetic etiology is largely unknown. In
dogs, a clinically and histologically similar disease disproportionately
affects two breeds, the Belgian Tervuren and Belgian Sheepdog, who develop
the intestinal and diffuse tumor subtypes observed in humans. We performed
a Bayesian genome-wide association study and selection analyses in this
naturally-occurring canine model to elucidate underlying genetic risk
factors for gastric cancer and identified 15 associated loci. Variant
filtering revealed germline putative regulatory variants for the EPAS1
(HIF2A) and PTEN genes and a coding variant in CD101. Two loci are
overrepresented among cases of intestinal tumor subtype. Although closely
related to Tervuren and Sheepdogs, Belgian Malinois rarely develop gastric
cancer. Across-breed analyses uncovered haplotypes enriched in Malinois at
SOX2-OT and IGF2BP2 that are at significantly higher frequency among GWAS
controls. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants
were present at comparatively high frequency and were associated with risk
of gastric cancer. Here, we describe a complex genetic architecture
governing gastric cancer in a dog model, including genes such as PDZRN3
and KLHL29, that have not been associated with human gastric cancer.