Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 847-861 |
| Number of pages | 15 |
| Journal | Molecular Cancer Research |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2021 |
Bibliographical note
Funding Information:J.H. Kim reports grants from NIH/NCI, AKC Canine Health Foundation, National Canine Cancer Foundation, Morris Animal Foundation, Swedish Cancer-fonden, Swedish Research Council, and Oscar J. Fletcher Distinguished Professorship during the conduct of the study. K. Megquier reports grants from NCI during the conduct of the study. R. Thomas reports grants and personal fees from Canine Health Foundation during the conduct of the study. E.K. Karlsson reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
The authors would like to acknowledge Dr. Corrie Painter for reviewing the manuscript and providing feedback. The authors acknowledge Mitzi Lewellen for assistance with inventory, database management, and editorial assistance. The authors would also like to thank Lauren Mills for processing of the next generation sequencing data and Dr. Douglas Yee, Director of Masonic Cancer Center, for assisting with the collection of human tissues. Human biospecimens were obtained from the UMN BioNet and from the CHTN. Tissue samples were provided by the CHTN which is funded by the NCI. Other investigators may have received specimens form the same subjects. This work was partially supported by grants 1R03CA191713-01 (to J.F. Modiano, A.L. Sarver, and J.H. Kim) and R37CA218570 (to E.K. Karlsson) from the NCI of the NIH, grants #422 (to J.F. Modiano) and 1889-G (to J.F. Modiano, M. Breen, and K. Lindblad-Toh) from the AKC Canine Health Foundation, grant JHK15MN-004 (to J.H. Kim) from the National Canine Cancer Foundation, grant D10-501 (to J.F. Modiano, M. Breen, and K. Lindblad-Toh) from Morris Animal Foundation, and a grant from Swedish Cancerfonden (to K. Lindblad-Toh). This work was also supported by an NIH NCI R50 grant, CA211249 (to A.L. Sarver). The NIH Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota (P30 CA077598) provided support for the cytogenetic analyses performed in the Cytogenomics Shared Resource. K. Megquier is supported by the NCI of the NIH under Award Number F32CA247088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M. Breen is supported in part by the Oscar J. Fletcher Distinguished Professorship in Comparative Oncology Genetics at North Carolina State University. K. Lindblad-Toh is supported by a Distinguished Professor award from the Swedish Research Council. J.F. Modiano is supported by the Alvin and June Perlman Chair in Animal Oncology. The UMGC (http://genomics.umn.edu) supported for generation of genomic sequencing data libraries, and the Minnesota Supercomputing Institute (MSI) at the University of Minnesota (http://www.msi.umn.edu) provided computational resources that contributed to the results in this study. The authors gratefully acknowledge donations to the Animal Cancer Care and Research Program of the University of Minnesota that helped support this project.
Funding Information:
from the UMN BioNet and from the CHTN. Tissue samples were provided by the CHTN which is funded by the NCI. Other investigators may have received specimens form the same subjects. This work was partially supported by grants 1R03CA191713-01 (to J.F. Modiano, A.L. Sarver, and J.H. Kim) and R37CA218570 (to E.K. Karlsson) from the NCI of the NIH, grants #422 (to J.F. Modiano) and 1889-G (to J.F. Modiano, M. Breen, and K. Lindblad-Toh) from the AKC Canine Health Foundation, grant JHK15MN-004 (to J.H. Kim) from the National Canine Cancer Foundation, grant D10-501 (to J.F. Modiano, M. Breen, and K. Lindblad-Toh) from Morris Animal Foundation, and a grant from Swedish Cancerfonden (to K. Lindblad-Toh). This work was also supported by an NIH NCI R50 grant, CA211249 (to A.L. Sarver). The NIH Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota (P30 CA077598) provided support for the cytogenetic analyses performed in the Cytogenomics Shared Resource. K. Meg-quier is supported by the NCI of the NIH under Award Number F32CA247088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M. Breen is supported in part by the Oscar J. Fletcher Distinguished Professorship in Comparative Oncology Genetics at
Publisher Copyright:
2021 American Association for Cancer Research.
