Highlights
- •PTEN is recurrently deleted in canine osteosarcoma while it is silenced by methylation in human osteosarcoma.
- •The extent of deletion or silencing is strongly associated with a set of genes that are increased in cycling cells and associated with poor outcome.
- •Provides direct molecular rational for tumor heterogeneity observed in both canine and human albeit by different mechanisms.
- •This breaks with the dogma that human and canine cancer are driven by the same molecular processes.
- •Strongly suggests that canines are at increased risk of osteosarcoma due to their genomic organization where the PTEN gene is located at the end of a small chromosome where both copies can be lost.
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. Comparative
models of tumorigenesis may utilize different driver mechanisms.
Keywords
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Article info
Publication history
Accepted:
May 19,
2023
Received in revised form:
March 2,
2023
Received:
October 28,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Published by Elsevier Inc.
