Discovery and Pathogenetic Significance of Chromosome Translocations in Angiosarcom

? DESCRIPTION (provided by applicant): Angiosarcomas are rare, highly aggressive cancers that originate from blood vessel-forming cells. Our understanding of the pathology of angiosarcomas is rudimentary; these tumors are diagnosed infrequently (fewer than 200 cases in the US each year) and they display extensive heterogeneity. This has made the development of effective therapies challenging. More than half of the patients with this disease die within the first year of diagnosis and tumor related mortality is extremely high. It is evident that a differet paradigm is needed to address the pathology and to develop effective treatments for this disease. The Opportunity: Hemangiosarcomas occur spontaneously and commonly in dogs (tens of thousands of cases in the US each year). Human angiosarcoma and canine hemangiosarcoma are morphologically and clinically indistinguishable. Molecular drivers of cancer progression are highly conserved among mammals. Specifically, we have documented the presence of orthologous non-random, recurrent chromosomal abnormalities in various tumors of humans and dogs that share anatomical and morphological features and that have comparable natural histories. This evolutionary conservation is not restricted to chromosomal aberrations; rather, it is apparent at the level of gene and microRNA expression. This provides a fundamental opportunity to reverse direction in comparative oncology and use canine tumors as a discovery system to identify potential, causative or pathognomonic events for homologous human diseases. We showed recently that canine hemangiosarcomas could be categorized into three molecular subtypes based on cell-autonomous properties and on their interactions with the microenvironment. Despite their complex, chaotic karyotypes, we identified a spectrum of recurrent inter-chromosomal fusion events (translocations) using next generation RNA sequencing. These were significantly associated with the different molecular subtypes, allowing us to consider development of specific targeted therapies to attack this disease. The plan: We will perform high-resolution RNA sequencing of idiopathic human angiosarcoma and non- malignant control tissues. The hypotheses are that the tumors will segregate into molecular subtypes that will be homologous to those we described for canine hemangiosarcoma, and that each subtype will be associated with translocations that will be orthologous to those found in the canine disease. We have selected to support this study through the R03 (discovery) mechanism as a means to provide proof-of-concept for additional studies as well as to develop a valuable resource for the scientific community working on sarcoma biology (RNA sequencing data for angiosarcomas does not exist in the public domain). The results from this project will enable us to embark on innovative, mechanistic projects to enhance our understanding of, and our capacity to manage this intractable disease.