| Summary |
Well-defined, closed breeding populations coupled with excessive disease predispositions among purebred domestic dog breeds offer unique advantages to genetic studies of disease susceptibility. Advantages offered by canine population substructure, combined with similarity to human disease in terms of clinical presentation and response to treatment, make 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). By combining genome-wide association studies from two geographic populations of BMD followed by fine mapping and sequencing, we have identified a cancer-associated haplotype within the MTAP/CDKN2A locus that is present in 95% 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. These results demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and yet poorly understood genomic region.
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