Abstract 3399: Comparative genomic analyses of osteosarcoma etiology reveal a chromosomal structural rationale for the increased incidence of osteosarcoma in dogs

Abstract

Abstract Risk of osteosarcoma is significantly higher in large and giant breed dogs than in any other animal, including humans. To identify the reason for this observation, we used a comparative genomic approach to identify aberrations responsible for osteosarcoma etiology in a Sleeping Beauty transposon-accelerated mouse model, in human patients, and in naturally occurring canine tumors, using RNA-Seq and exome paired tumor normal analyses. Fusions identified in Sleeping Beauty-mutagenized tumors revealed a role for Cdkn2a disruption in Trp53 signaling, and for numerous genes which cooperate with disrupted TrpP53 signaling, indicating the existence of many diverse routes to osteosarcoma tumor formation. Similarly, human tumors showed TP53 pathway disruption associated with a high level of diversity of additional driver mechanisms, supporting multiple independent routes to tumor formation. However, in the majority of canine tumors, observed TP53 pathway aberrations co-occurred with loss of both copies of the region containing the PTEN tumor suppressor. In human osteosarcoma, only heterozygous PTEN loss was observed, and in both humans and mice, PTEN aberration was observed in a much smaller percentage of the tumor population. We hypothesize that increased osteosarcoma incidence in dogs is partly due to a syntenic rearrangement of the peri-PTEN locus in the canine genome. The PTEN gene is part of a small synteny block that localized in the distal end of canine chromosome 26 (CFA 26) during evolution. We hypothesize that this location change creates a high risk of loss in the context of cytogenetic instability caused by disruption of TP53, thereby providing a structural genetic rational for the higher incidence of osteosarcoma in dogs. Consistent with these results and with the powerful nature of PTEN as a tumor suppressor, canine osteosarcomas with homozygous loss of PTEN are associated with worse outcomes than canine osteosarcomas with intact PTEN. These results suggest that engineering genomes to minimize cancer risk may be a realistic approach to the prevention of cancer. Citation Format: Aaron L. Sarver, Lauren Mills, Nuri Temiz, MIlcah Scott, Anne Sarver, Logan Spector, Jinhua Wang, Mathew Breen, Subbaya Subramanian, Branden Moriarity, Jaime Modiano, David Largaespada. Comparative genomic analyses of osteosarcoma etiology reveal a chromosomal structural rationale for the increased incidence of osteosarcoma in dogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3399.