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Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog, NIPAL1, and the MAPK signaling pathway

ABSTRACT: Naturally occurring canine invasive urinary carcinoma (iUC) closely mimics human high grade iUC in terms of age of onset, pathology, cellular and molecular features, metastatic profiles, and treatment response . Shetland sheepdogs (Shelties), the focus of this study, are a small herding breed and popular family pet. Multiple studies demonstrate their extraordinary disease risk, with one survey reporting that of 3359 Shelties, iUC comprised 12% of all Sheltie cancer diagnoses, which is six times the expected rate of 2% for all dogs. In this study we analyze one hundred Shelties and 55 dogs from closely related breeds and identify a single major risk locus associated with iUC, featuring NIPA-like domain containing 1 (NIPAL1), a strong candidate gene, and associated mutations. By segregating samples according to genotype, we identify six additional loci that modify individual disease risk when combined with a putative pathogenic protein altering mutation in NIPAL1. Merging the GWAS loci with tumor sequence identifies the mitogen activated protein kinase (MAPK) signaling pathway as a key component of canine iUC genetic susceptibility.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE254079 | GEO | 2024/01/31

REPOSITORIES: GEO

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