The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer

Abstract

Background Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD). Methods Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. 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.

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…Specially, recurrent deletions were detected in commonly described human tumour suppressor genes, including CDKN2A/B, RB1 and PTEN [86]. Interestingly, the GWAS of canine HS in BMDs (see above) localized a possible HS-risk allele also to CDKN2A (in addition to MTAP) [38]. Hedan et al [86] also identified several private CNAs unique and recurrent to each breed, perhaps suggesting a difference in initiation and/or progression leading to a more universal HS genomic phenotype once the tumour develops.…”

“…This exceedingly rare sarcoma in humans occurs frequently in a few breeds of dog, including BMD, flat-coated retriever, Rottweiler and golden retriever. The lifetime risk of developing a HS in BMDs is 15-25% [38,39]. The authors performed the first GWAS in 111 BMD cases and 117 BMD controls from North America, as well as a second GWAS in 125 BMD cases and 117 BMD controls from Europe.…”

A longitudinal study of ABC transporter expression in canine multicentric lymphoma

“…Breeding from within a selected population of dogs can, in a relative short period of time, give rise to a clear change in phenotype which leads to breed development [1,2] but may also cause an increase in the occurrence of inherited diseases [3][4][5][6][7] such as cancer [8][9][10][11][12]. Clear evidence exists for a breed-related predisposition to specific cancers, like histiocytic sarcomas in Bernese Mountain dogs [10,13] and Flatcoated retrievers, [11] anal sac carcinomas in the English Cocker Spaniel [12,14] and hemangiosarcomas in German Shepherd dogs [15].…”

The 2013 Genetics Society of America Medal

“…Elaine has also used her powerful genome-wide strategies to uncover polymorphisms involved in a variety of canine cancers. Because a poorly understood sarcoma that is rare in humans is quite common in Bernese mountain dogs, her group was able to find a haplotype common to the vast majority of affected animals, thereby pinpointing defective regulation of genes that had been implicated in human cancer (Shearin et al 2012). Elaine has articulated persuasively how the high resemblance of some canine and human diseases, the knowledge gained from veterinary medicine, and the ability to identify the genes underlying breed-associated diseases make dogs such a compelling model for human medical genetics (Ostrander 2012a).…”