Finding Genes and Pathways for Canine Cancers Dr Ingegerd Elvers, Kerstin Lindblad-Toh lab Broad Institute, MA, USA, and SciLife Lab, Uppsala University, Uppsala, Sweden Dogs and humans share many diseases where genetic background and environment play a role, such as several forms of cancer. The dog population structure, with distinct breeds derived from small founder populations, makes trait mapping considerably easier than in humans. Power calculations and proof of principle studies have shown that 100-300 cases and 100-300 controls can suffice to map risk factors contributing a 2-5 fold increased risk in dogs (Lindblad-Toh et al, Nature 2005). Dogs have been used successfully to map complex diseases including systemic lupus erythematosus, obsessive-compulsive disorder and osteosarcoma (Wilbe et al, Nat Genet 2010; Dodman et al, Mol Psych 2010; Karlsson et al, Genome Biol 2013). In our research, we have focused on cancers where the genetic complexity and/or relative rarity limit studies in humans, such as osteosarcoma, lymphoma, and hemangiosarcoma. Our research shows several important principles for canine cancer that may be extrapolated to human cancers: A. Common risk factors for two diseases: B-cell lymphoma and hemangiosarcoma are two highly aggressive hematopoietic cancers, both common in golden retrievers. Using genome-wide association (GWA) we find two unlinked loci on canine chromosome 5 that explain ~20 % of total risk in the US golden retriever population to develop both canine B-cell lymphoma and hemangiosarcoma. We identify several, partially overlapping haplotypes in these two loci. Using gene expression data from RNA-Seq of tumors, the effect of the different haplotypes on gene expression can be compared. Genes alternatively regulated by the risk haplotype implicates local microenvironment and T-cell activation together with B-cell growth and angiogenesis. B. Alternative pathways in different breeds with osteosarcoma: Osteosarcoma is a relatively rare and poorly understood cancer characterized by early metastasis and high mortality. Global tumor gene expression signature indistinguishable from tumors from human pediatric patients and, while age of onset is higher in dogs, the clinical progression is remarkably similar. Both human and canine osteosarcomas most commonly arise at the ends of the long bones of the limbs and metastasize readily, usually to the lungs (F. Mueller, B. Fuchs, B. KaserHotz, Comparative biology of human and canine osteosarcoma. Anticancer research 27, 155 (Jan-Feb, 2007)).Canine studies indicate that hormonal factors and size plays a role, but distinct breed differences indicate genetic factors. GWA studies using up to 100 cases and controls per breed identified 33 associated loci, with no overlap between breeds. We identify 6-15 loci per breed explaining 40-80% of the phenotypic variation. Interestingly, the greyhound top associated locus is near the p15/p16 genes and further analysis of this locus has shown that rottweilers and Irish wolfhounds are fixed for the greyhound risk haplotype. Serial luciferase assays also identifies an enhancer that harbors the best candidate mutation on the risk haplotype. Pathway analysis of GWAs regions, regions of fixed regions in each breed together with CGH data identifies both common and breed specific disease pathways. Notably, the top candidate mutations in all three cancers fall outside proteincoding sequence. In addition to looking for predisposing regions and mutations, we have performed exome sequencing of paired tumor-normal samples from over a hundred dogs with B- or T-cell lymphoma. Using three different dog breeds with different predisposition to B- and T-cell lymphoma, we can look at differences and similarities in affected genes and pathways. The breeds constitute patient groups with different genetic backgrounds. Breed comparison shows that the B-cell lymphoma predisposed breeds have more overlap in somatic mutations compared to the T-cell lymphoma predisposed breeds. Somatic copy number alterations and coding mutations partially implicate the same genes. Of the significantly mutated genes in this comparison of B- and T-cell lymphoma predisposed breeds, about half overlap have previously been implicated in human lymphoma or leukemia. We hope that the novel genes could enable new lymphoma treatment options. The use of multiple dog breeds and functional assays together with the extensive genome annotation available on the human genome can help decipher the regulatory mechanisms underlying disease. We conclude that pet dogs offer an outstanding opportunity to help dissect complex cancers.