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

VL - 12

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 5

M1 - e1006029

ER -