TY - JOUR
T1 - Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours
AU - Melin, Malin
AU - Rivera, Patricio
AU - Arendt, Maja
AU - Elvers, Ingegerd
AU - Murén, Eva
AU - Gustafson, Ulla
AU - Starkey, Mike
AU - Borge, Kaja Sverdrup
AU - Lingaas, Frode
AU - Häggström, Jens
AU - Saellström, Sara
AU - Rönnberg, Henrik
AU - Lindblad-Toh, Kerstin
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
KW - Animals
KW - Breast Neoplasms/genetics
KW - Dog Diseases/genetics
KW - Dogs
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Haplotypes
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Mammary Neoplasms, Animal/genetics
KW - Nerve Tissue Proteins/genetics
KW - RNA, Small Nucleolar/genetics
U2 - 10.1371/journal.pgen.1006029
DO - 10.1371/journal.pgen.1006029
M3 - Journal article
C2 - 27158822
SN - 1553-7390
VL - 12
JO - PLOS Genetics
JF - PLOS Genetics
IS - 5
M1 - e1006029
ER -
