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Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma.

ABSTRACT: Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that shares many similarities with spontaneously occurring hemangiosarcoma (HSA) in dogs and cats. To investigate the genetic suitability of HSA as a model for AS, we sequenced ∼1000 cancer genes in 41 cases of HSA and matched germline tissue: 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of HSA to AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs and both species show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrates many important parallels to AS and provides hope that future studies on these cancers will benefit of all three species.

SUBMITTER: Wong K

PROVIDER: S-EPMC8319545 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma.

Wong Kim K Ludwig Latasha L Krijgsman Oscar O Adams David J DJ Wood Geoffrey A GA van der Weyden Louise L

Disease models & mechanisms 20210723 7

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that shares many similarities with spontaneously occurring hemangiosarcoma (HSA) in dogs and cats. To investigate the genetic suitability of HSA as a model for AS, we sequenced ∼1000 cancer genes in 41 cases of HSA and matched germline tissue: 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showe ...[more]

PMID: 34296746

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Project description:Sporadic angiosarcomas 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 angiosarcomas. In this study, we leveraged RNA-sequencing data from 13 human angiosarcomas and 76 spontaneous canine hemangiosarcomas 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 13 human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in angiosarcomas without fusions or TP53 mutations. We found 15 novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in 11 of the 76 canine hemangiosarcomas; 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 cooccurred 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 angiosarcomas and canine hemangiosarcomas identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data suggest that genome 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. IMPLICATIONS: This study shows that, while drive 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 morphologic organization and biological behavior of these tumors in both species.

Dataset Information

Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma.

Publications

Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma.

Similar Datasets

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