Abstract
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.
Highlights
Over the past decade, dogs have emerged as a relevant and under-used spontaneous model for the analysis of cancer predisposition and progression as well as development and trials of more efficient therapies for many human cancers [1,2,3,4,5,6,7,8,9,10]
From 10,3487 single nucleotide variation (SNV) left after applying filters, we identified 21 SNVs that were significantly associated with histiocytic sarcoma (HS), including 20 SNVs on chromosome 11 spanning 40.3–47.2 Mb and one SNV on chromosome 20 (CFA20:30,922,308, pcorrected = 3.73 × 10−5)
An additional SNV on chromosome 5 (CFA5:30,496,048, pcorrected = 9.48. × 10−5) was close to the genome-wide significance, and was suspected to be associated with HS. This genome-wide association studies (GWAS) confirmed that the main locus linked to HS was located on CFA11, overlapping the methyl-50-thioadenosine phosphorylase (MTAP)-cyclindependent kinase inhibitor 2A (CDKN2A) region, a locus previously associated with HS [26]
Summary
Dogs have emerged as a relevant and under-used spontaneous model for the analysis of cancer predisposition and progression as well as development and trials of more efficient therapies for many human cancers [1,2,3,4,5,6,7,8,9,10]. Because of specific breed structures and artificial selection, dog breeds have gained numerous susceptibilities to genetic diseases, and a limited number of their critical genes are involved in complex diseases such as cancers [6]. Numerous genome-wide association studies (GWAS) in dogs have illustrated that with complex traits, such as body size and cancer, a small number of loci with strong effects are involved in dogs, as compared to humans, thereby facilitating their identification. Spontaneously affected pet dogs, with breed-specific cancers, provide efficient natural models to identify the genetics underlying several dog-human homologous cancers
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