SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma

Sharadha Sakthikumar, Ingegerd Elvers, Jaegil Kim, Maja L. Arendt, Rachael Thomas, Jason Turner-Maier, Ross Swofford, Jeremy Johnson, Steven E. Schumacher, Jessica Alfoldi, Erik Axelsson, C. Guillermo Couto, William C. Kisseberth, Mats E. Pettersson, Gad Getz, Jennifer R.S. Meadows, Jaime F. Modiano, Matthew Breen, Marcin Kierczak, Karin Forsberg-NilssonVoichita D. Marinescu, Kerstin Lindblad-Toh

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3421-3431
Number of pages11
JournalCancer Research
Volume78
Issue number13
DOIs
StatePublished - Jul 1 2018

Bibliographical note

Funding Information:
Funding is gratefully acknowledged from the NIH (U54 HG003067-08, awarded to the Broad Institute), the European Research Council (ERC), the Go€ran Gustafsson Foundation, Swedish Cancer Foundation, the American Kennel Club (AKC) Canine Health Foundation, the Golden Retriever Foundation, and the National Cancer Institute (NCI) for the OSU tissue bank (P30 CA016058). I. Elvers is supported by a postdoctoral fellowship from the

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