Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma

Aaron L Sarver; Lauren J Mills; Kelly M Makielski; Nuri A Temiz; Jinhua Wang; Logan G Spector; Subbaya Subramanian; Jaime F Modiano

doi:10.1016/j.cancergen.2023.05.001

Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma

Cancer Genet. 2023 Aug:276-277:1-11. doi: 10.1016/j.cancergen.2023.05.001. Epub 2023 May 20.

Authors

Aaron L Sarver¹, Lauren J Mills², Kelly M Makielski³, Nuri A Temiz⁴, Jinhua Wang⁴, Logan G Spector⁵, Subbaya Subramanian⁶, Jaime F Modiano⁷

Affiliations

¹ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA. Electronic address: sarver@umn.edu.
² Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
³ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA.
⁴ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.
⁶ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Surgery, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
⁷ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Center for Engineering and Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

PMID: 37267683
DOI: 10.1016/j.cancergen.2023.05.001

Abstract

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.

Keywords: Bioinformatics; Cancer; Comparative genomics; Genomics; Osteosarcoma.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Bone Neoplasms* / genetics
Bone Neoplasms* / pathology
Cell Division
Dogs
Homozygote
Humans
Osteosarcoma* / genetics
Osteosarcoma* / pathology
PTEN Phosphohydrolase / genetics
Sequence Deletion

Substances

PTEN protein, human
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding