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

PLoS Genet. 2016 May 9;12(5):e1006029. doi: 10.1371/journal.pgen.1006029. eCollection 2016 May.

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.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins
  • Dog Diseases / genetics*
  • Dog Diseases / pathology
  • Dogs
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / pathology
  • Nerve Tissue Proteins / genetics
  • RNA, Small Nucleolar / genetics

Substances

  • CDK5RAP2 protein, human
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • RNA, Small Nucleolar

Grant support

This study was supported by the Swedish Research Council and the European Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.