journal contribution
posted on 2023-04-03, 19:47 authored by Jong Hyuk Kim, Kate Megquier, Rachael Thomas, Aaron L. Sarver, Jung Min Song, Yoon Tae Kim, Nuojin Cheng, Ashley J. Schulte, Michael A. Linden, Paari Murugan, LeAnn Oseth, Colleen L. Forster, Ingegerd Elvers, Ross Swofford, Jason Turner-Maier, Elinor K. Karlsson, Matthew Breen, Kerstin Lindblad-Toh, Jaime F. Modiano S1. Representative putative inter-chromosomal fusion transcripts in human AS and canine HSA. SCLT1-NIPBL fusion in human angiosarcoma. S2. Fusion genes and their association with tumor content and sequencing depth in canine HSA tissues. S3. A, Primers designed for amplification of SCLT1-NIPBL fusion transcripts identified in human angiosarcoma. B, SCLT1-NIPBL fusion gene amplification by quantitative RT-PCR. Expression value represents 2(-â^†Ct)(Fusion gene/GAPDH). C, Primers designed for amplification of four fusion transcripts identified in canine hemangiosarcomas. D, Fusion gene amplification was confirmed in canine tumors by quantitative RT-PCR. E, Electrophoresis (1% agarose gel) of DNA product by RTPCR was done. S4. Genetic alterations of fusion partner genes identified in human AS. S5. Cell type enrichment analysis in ASs and TCGA sarcomas. S6. Three distinct molecular groups of canine HSAs. S7. Kaplan-Meier probability of survival for dogs with angiogenic and inflammatory HSA. S8. Association of the fusion events with demographic and histopathologic features in canine HSA. S9. Gene pathways associated with commonly enriched genes in tumors with fusion genes and TP53 mutations in canine HSA. S10. Violin plots display IHC scores of p53, p-p53 (Ser15), and p-p53 (Ser20) in human AS and canine HSA. S11. Violin plots present IHC scores of AKT and p-AKT (Thr308) in human AS and canine HSA. S12. IHC scores of mTOR and p-mTOR (Ser2448) in human AS.
Funding
NCI
AKC Canine Health Foundation
National Canine Cancer Foundation
Morris Animal Foundation
NIH
Masonic Cancer Center, University of Minnesota
History
ARTICLE 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.
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.
