期刊
CANCER RESEARCH
卷 78, 期 13, 页码 3421-3431出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3558
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资金
- NIH [U54 HG003067-08]
- European Research Council (ERC)
- Goran Gustafsson Foundation
- Swedish Cancer Foundation
- American Kennel Club (AKC) Canine Health Foundation
- Golden Retriever Foundation
- National Cancer Institute (NCI) [P30 CA016058]
- Swedish Medical Research Council, SSMF
- Swedish Research Council, FORMAS
- Alvin S. and June Perlman Chair in Animal Oncology at the University of Minnesota
- Oscar J. Fletcher Distinguished Professorship in Comparative Oncology Genetics at NC State University
- Swedish Research Council
- European Research Council
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.
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