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.
Highlights
Breast cancer is a devastating disease causing a majority of cancer-related deaths in women worldwide [1]
genome-wide association study (GWAS) identifies three regions significantly associated with Canine mammary tumours (CMT)
The inflation was controlled by removal of an outlier group of 33 individuals, and by mixed model analysis with PCA covariates to correct for residual stratification and cryptic relatedness in the remaining 180 cases and 119 controls (λ = 1.00, Fig 1A)
Summary
Breast cancer is a devastating disease causing a majority of cancer-related deaths in women worldwide [1]. There is an urgent need to identify predisposing genes and prognostic tools to improve early detection and enhanced treatment options in breast cancer. Breast cancer susceptibility is generally believed to be conferred by a large number of loci, each contributing with a small effect to breast cancer risk [3]. Several genes predisposing to breast cancer have been identified, including BRCA1 and BRCA2, which explain about 20% of the familial breast cancer cases [6]. A large number of association studies have been performed in search of breast cancer susceptibility genes, including pooled strategies and meta-analyses, and many genes conferring a moderately increased risk have been identified [7,8,9,10]. A large proportion of the inherited risk factors remain unknown
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