title: 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.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Department of Immunology, genetics and pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Melin
authors.affiliation: Evidensia Södra Djursjukhuset, Stockholm, Sweden.
authors.forename: Patricio
authors.identifier: 0000-0003-2542-5905
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maja
authors.initials: M
authors.lastname: Arendt
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Ingegerd
authors.identifier: 0000-0002-6604-0369
authors.initials: I
authors.lastname: Elvers
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Murén
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Gustafson
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Starkey
authors.affiliation: Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
authors.forename: Kaja Sverdrup
authors.initials: KS
authors.lastname: Borge
authors.affiliation: Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
authors.forename: Frode
authors.initials: F
authors.lastname: Lingaas
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Jens
authors.identifier: 0000-0003-3402-023X
authors.initials: J
authors.lastname: Häggström
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Saellström
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Rönnberg
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D020537:RNA, Small Nucleolar / Q000235:genetics
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020537:RNA, Small Nucleolar