title: The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer.
abstract: BACKGROUND
  Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD).
  
  
  METHODS
  Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region.
  
  
  RESULTS
  Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer.
  
  
  CONCLUSIONS
  We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds.
  
  
  CONCLUSIONS
  Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Shearin
authors.forename: Benoit
authors.initials: B
authors.lastname: Hedan
authors.forename: Edouard
authors.initials: E
authors.lastname: Cadieu
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Erich
authors.forename: Emmett V
authors.initials: EV
authors.lastname: Schmidt
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Faden
authors.forename: John
authors.initials: J
authors.lastname: Cullen
authors.forename: Jerome
authors.initials: J
authors.lastname: Abadie
authors.forename: Erika M
authors.initials: EM
authors.lastname: Kwon
authors.forename: Andrea
authors.initials: A
authors.lastname: Gröne
authors.forename: Patrick
authors.initials: P
authors.lastname: Devauchelle
authors.forename: Maud
authors.initials: M
authors.lastname: Rimbault
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Karyadi
authors.forename: Mary
authors.initials: M
authors.lastname: Lynch
authors.forename: Francis
authors.initials: F
authors.lastname: Galibert
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Rutteman
authors.forename: Catherine
authors.initials: C
authors.lastname: André
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Parker
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004198:Disease Susceptibility; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005060:Europe; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009369:Neoplasms / Q000209:etiology*; D009656:North America; D025341:Principal Component Analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D008869:Microtubule-Associated Proteins