The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer.
Abstract
BACKGROUND: Advantages offered by canine population substructure, combined with clinical similarity to human disease makes the dog a particularly attractive system for finding genes associated with cancer. Cancers that have been difficult to study in human families or populations are of particular interest, especially those associated with one or a small number of breeds and a high level of occurrence. Histiocytic sarcoma (HS) is a rare and poorly understood neoplasm in humans, however it occurs in 15-25% of Bernese Mountain Dogs (BMD). METHODS: Genomic DNA was collected from affected and unaffected BMD in both North America and Europe. Both independent and combined genome wide association studies (GWAS) from the two geographic populations were used to identify cancer associated loci. Fine mapping and sequencing was used to narrow the primary locus.RESULTS: GWAS revealed a cancer-associated locus shared by both populations. The locus contains a single haplotype spanning MTAP and part of CDKN2A that is present in 96% of all affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in numerous complex genetic diseases including several cancers. CONCLUSIONS: We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Impact: Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region.