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Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID iD: 0000-0002-1458-0865
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota..
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2019 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 17, no 12, p. 2410-2421Article in journal (Refereed) Published
Abstract [en]

Angiosarcoma is a highly aggressive cancer of blood vessel-forming 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.

Place, publisher, year, edition, pages
2019. Vol. 17, no 12, p. 2410-2421
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-399825DOI: 10.1158/1541-7786.MCR-19-0221ISI: 000500951800006PubMedID: 31570656OAI: oai:DiVA.org:uu-399825DiVA, id: diva2:1379236
Funder
Swedish Cancer SocietySwedish Research CouncilAvailable from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-01-13Bibliographically approved
In thesis
1. Characterizing the spectrum of somatic alterations in canine and human cancers
Open this publication in new window or tab >>Characterizing the spectrum of somatic alterations in canine and human cancers
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancers arise as a result of deleterious somatic alterations accumulating in the genome during the process of cell division. These alterations arise either via exposure to mutagens or due to errors occurring during DNA replication. In this thesis, a systematic exploration, from discovery to analyses of somatic alterations in three diverse cancers that affect dogs and humans, was undertaken.

In Studies I and II, whole-exome sequencing of dogs affected by the cancers of osteosarcoma and hemangiosarcoma were done to delineate coding mutations that can contribute to their carcinogenesis. Besides, as these cancers mirror the corresponding human disease in clinical manifestation and histological features, a secondary objective was to confirm the molecular drivers found in the canines were also influencing factors in the human cancer(s).

In the osteosarcoma investigations with three breeds, we found that tumors show a high frequency of somatic copy-number alterations, affecting key cancer genes. TP53 was the most frequently altered gene, akin to human osteosarcoma. The second most mutated gene, histone methyltransferase SETD2, has known epigenetic roles in multiple cancers but not in osteosarcoma. Our study highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine disease may serve as an excellent model for developing treatment strategies in both species.

In the hemangiosarcoma study in golden retrievers, putative driver alterations were identified in the tumor suppressor TP53 and in genes involved in the cell cycle regulating PI3K pathway, including PIK3CA and PIK3R1. Furthermore, we find several somatic alterations between the dog hemangiosarcoma and human angiosarcoma overlap, indicating we can use the canine model to apprise the infrequently occurring human disease.

In Study III, we implemented whole-genome sequencing methodologies to define both coding and non-coding alterations in the glioblastoma cancer genome. We find the coding somatic alterations recapitulate what has been previously seen for the cancer, including driver alterations in the genes of EGFR, PTEN, and TP53. Significantly though, using the concept of evolutionary constraint, we find an enrichment of non-coding mutations in regulatory regions, around GBM-implicated genes. The mutated regions include splice sites, promoters, and transcription factor binding sites, suggesting the importance of regulatory mutations for the pathogenesis of glioblastoma.

Overall, the insights garnered from the above exome- and genome-wide surveys provide novel insights into unraveling some of the complexities associated with somatic genomic alterations in cancer genomes. It also convincingly underscores the benefits of using sequencing technologies to comprehend complex biological diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1624
Keywords
dog, osteosarcoma, hemangiosarcoma, glioblastoma, non-coding, whole-exome, whole-genome, sequencing, bioinformatics, comparative genetics.
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-399978 (URN)978-91-513-0839-5 (ISBN)
Public defence
2020-02-20, B41, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:14 (English)
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Supervisors
Available from: 2020-01-31 Created: 2019-12-17 Last updated: 2020-01-31

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Megquier, KatherineWang, ChaoSakthikumar, SharadhaElvers, IngegerdLindblad-Toh, Kerstin

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