A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma. Reduction in PTEN copy number was observed in 23 of 95 (25%) of the canine tumors examined leading to corresponding decreases in PTEN transcript levels from RNA-Seq samples. Unexpectedly, canine tumors with an intact PTEN locus had higher levels of PTEN transcripts than human tumors. This variation in transcript abundance was used to evaluate the role of PTEN in osteosarcoma biology. Decreased PTEN copy number and transcript level was observed in - and likely an important driver of - increases in cell cycle transcripts in four independent canine transcriptional datasets. In human osteosarcoma, homozygous copy number loss was not observed, instead increased methylation of the PTEN promoter was associated with increased cell cycle transcripts. Somatic modification of PTEN, either by homozygous deletion in dogs or by promoter methylation in humans, is clinically relevant to osteosarcoma, because the cell cycle related transcripts are associated with patient outcomes. The PTEN gene is part of a syntenic rearrangement unique to the canine genome, making it susceptible to somatic loss of both copies of distal chromosome 26 which also includes the FAS death receptor. Significance Statement: PTEN function is abrogated by different mechanisms in canine and human osteosarcoma tumors leading to uncontrolled cell cycling. Somatic loss of this canine specific syntenic region may help explain why the canine genome appears to be uniquely susceptible to osteosarcoma. Syntenic arrangement, in the context of copy number change, may lead to synergistic interactions that in turn modify species specific cancer risk. Comparative models of tumorigenesis may utilize different driver mechanisms.
Bibliographical noteFunding Information:
This work was generously supported by the Zach Sobiech Osteosarcoma Fund and the Team Nat Fund of the Children's Cancer Research Fund (CCRF), the Karen Wyckoff Rein in Sarcoma Foundation, GREYlong, and the Van Sloun Foundation; by grants R50 CA211249 (ALS), P30 CA077598 (Masonic Cancer Center Comprehensive Cancer Center Support Grant), and R21 CA208529 (JFM) from the National Cancer Institute of the National Institutes of Health (NCI); and by grants CA170218 and CA190276 (JFM) from the United States Department of Defense Congressionally Directed Peer Reviewed Cancer Research Program. KMM was supported in part by an institutional training grant in Molecular, Genetic, and Cellular Targets of Cancer (Grant T32CA009138) from the NCI. JFM is supported in part by the Alvin and June Perlman Endowed Chair in Animal Oncology. The authors acknowledge support from individual donors to the Animal Cancer Care and Research Program, University of Minnesota. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies listed above.
- Comparative genomics
PubMed: MeSH publication types
- Journal Article
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural