Identification of common predisposing loci to hematopoietic cancers in four dog breeds

Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans
and dogs. The spontaneous canine model, which has clinical,
epidemiological, and histological similarities with human HS and specific
breed predispositions, provides a unique opportunity to unravel the
genetic basis of this cancer. In this study, we aimed to identify germline
risk factors associated with the development of HS in canine-predisposed
breeds. We used a methodology that combined several genome-wide
association studies in a multi-breed and multi-cancer approach as well as
targeted next-generation sequencing, and imputation We combined several
dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers,
and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and
mast cell tumor). Results showed that we not only refined the previously
identified HS risk CDKN2A locus, but also identified new loci on canine
chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific
loci suggested the existence of regulatory variants in non-coding regions
and methylation mechanisms linked to risk haplotypes, which lead to strong
cancer predisposition in specific dog breeds. We also showed that these
canine cancer predisposing loci appeared to be due to the additive effect
of several risk haplotypes involved in other hematopoietic cancers such as
lymphoma or mast cell tumors as well. This illustrates the pleiotropic
nature of these canine cancer loci as observed in human oncology, thereby
reinforcing the interest of predisposed dog breeds to study cancer
initiation and progression.