Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours

Abstract

Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.

A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans

“…This makes sense because strict pedigree barriers prevent interbreeding, suggesting that each breed represents an isolated population with potentially its own unique mutations and resultant diseases (Patterson ; Melin et al . ).…”

“…In both species, identified risk factors include age, obesity, hormonal effects and genetics (Rivera & von Euler ; ACS, ; Melin et al . ). A true understanding of the genetic contributions to BC has yet to be fully grasped due to the heterogeneity of the disease and studied human cohorts, and its apparent polygenic inheritance (Chandler et al .…”

“…; ACS, ; Melin et al . ). This, however, also highlights the importance of noting CMT and BC differences.…”

“…; Melin et al . ). While this breed may present an attractive model, it should be noted that spaying of dogs is uncommon in Sweden (Egenvall et al .…”

“…While WES is currently the most attractive and attainable NGS method due to cost and other constraints, analysing the entire canine genome through whole genome sequencing (WGS) is worthwhile since disease‐predisposing variants are not necessarily solely located in the coding DNA (Davis & Ostrander ; Melin et al . ). During these studies, ascertainment of clinical data including age, sex and tumour type are invaluable and could be individually tested for association with newly identified CMT‐risk variants.…”