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SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst, Cambridge, MA USA.
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 Inst, Cambridge, MA USA.
Broad Inst, Cambridge, MA USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg D, Denmark.
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed) Published
Abstract [en]

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2018. Vol. 78, no 13, p. 3421-3431
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-360424DOI: 10.1158/0008-5472.CAN-17-3558ISI: 000437214300003PubMedID: 29724721OAI: oai:DiVA.org:uu-360424DiVA, id: diva2:1249615
Funder
EU, European Research CouncilSwedish Research Council FormasSwedish Research CouncilEU, European Research CouncilAvailable from: 2018-09-19 Created: 2018-09-19 Last updated: 2019-12-17Bibliographically 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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Available from: 2020-01-31 Created: 2019-12-17 Last updated: 2020-01-31

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Sakthikumar, SharadhaElvers, IngegerdArendt, Maja LouiseAxelsson, ErikPettersson, MatsMeadows, JenniferKierczak, MarcinMarinescu, VoichitaLindblad-Toh, Kerstin
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