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

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. ChIP-Seq for 3 histone modifications H3K4me1, H3K4me3, and K3K27ac in 2 canine invasive urinary carcinoma cell line samples.