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bioRxiv · 10.1101/2024.08.14.604426

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

Cook, S. R.·Hugen, S.·Hayward, J. J.·Famula, T. R.·Belanger, J. M.·McNiel, E.·Fieten, H.·Oberbauer, A. M.·Leegwater, P. A.·Ostrander, E. A.·Mandigers, P. J.·Evans, J. M.
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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 the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative 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 as PDZRN3, that have not been associated with human GC.

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Cook, S. R., Hugen, S., Hayward, J. J., Famula, T. R., Belanger, J. M., McNiel, E., Fieten, H., Oberbauer, A. M., Leegwater, P. A., Ostrander, E. A., Mandigers, P. J., Evans, J. M.. 2024-08-16. Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer. https://doi.org/10.1101/2024.08.14.604426

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