Angiosarcoma is a highly aggressive cancer of blood vesselforming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease.Implications: We characterize the genomic landscape of canine hemangiosarcoma and demonstrate its similarity to human angiosarcoma.

Sporadic angiosarcomas (ASs) are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic ASs. In this study, we leveraged RNA sequencing data from thirteen human ASs and 76 spontaneous canine hemangiosarcomas (HSAs) to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the thirteen human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in ASs without fusions or TP53 mutations. We found fifteen novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in eleven of the 76 canine HSAs; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 co-occurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human ASs and canine HSAs identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data show that, while driver events of malignant vasoformative tumors of humans and dogs include diverse mutations and stochastic rearrangements that create novel fusion genes, convergent transcriptional programs govern the highly conserved morphological organization and biological behavior of these tumors in both species.

Cancer is among the most common causes of death for dogs (and cats) and humans in the developed world, even though it is uncommon in wildlife and other domestic animals. We provide a rationale for this observation based on recent advances in our understanding of the evolutionary basis of cancer. Over the course of evolutionary time, species have acquired and fine-tuned adaptive cancer-protective mechanisms that are intrinsically related to their energy demands, reproductive strategies, and expected lifespan. These cancer-protective mechanisms are general across species and/or specific to each species and their niche, and they do not seem to be limited in diversity. The evolutionarily acquired cancer-free longevity that defines a species' life history can explain why the relative cancer risk, rate, and incidence are largely similar across most species in the animal kingdom despite differences in body size and life expectancy. The molecular, cellular, and metabolic events that promote malignant transformation and cancerous growth can overcome these adaptive, species-specific protective mechanisms in a small proportion of individuals, while independently, some individuals in the population might achieve exceptional longevity. In dogs and humans, recent dramatic alterations in healthcare and social structures have allowed increasing numbers of individuals in both species to far exceed their species-adapted longevities (by two to four times) without allowing the time necessary for compensatory natural selection. In other words, the cancer-protectiveThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Sporadic angiosarcomas (ASs) are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic ASs. In this study, we leveraged RNA sequencing data from thirteen human ASs and 76 spontaneous canine hemangiosarcomas (HSAs) to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the thirteen human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in ASs without fusions or TP53 mutations. We found fifteen novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in eleven of the 76 canine HSAs; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 co-occurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human ASs and canine HSAs identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data suggest that genomic instability induced by TP53 mutations might create a predisposition for fusion events that may contribute to tumor progression by promoting selection and/or enhancing fitness through activation of convergent angiogenic pathways in this vascular malignancy.