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Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway

Saba, Karim H. LU orcid ; Difilippo, Valeria LU ; Kovac, Michal ; Cornmark, Louise LU ; Magnusson, Linda LU ; Nilsson, Jenny LU ; van den Bos, Hilda ; Spierings, Diana C.J. ; Bidgoli, Mahtab LU and Jonson, Tord LU , et al. (2023) In Journal of Pathology p.147-160
Abstract

TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and... (More)

TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma.

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organization
publishing date
type
Contribution to journal
publication status
in press
subject
keywords
gene fusion, osteosarcoma, p53, promoter swapping, separation-of-function mutation, TP53 intron 1, TP53 mutation, TP53 promoter, TP53 signalling pathway
in
Journal of Pathology
pages
14 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:38010733
  • scopus:85177795163
ISSN
0022-3417
DOI
10.1002/path.6219
language
English
LU publication?
yes
id
82849948-b87a-4817-ab39-d7e6d30a32c9
date added to LUP
2024-01-10 12:00:03
date last changed
2024-04-25 07:55:53
@article{82849948-b87a-4817-ab39-d7e6d30a32c9,
  abstract     = {{<p>TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma.</p>}},
  author       = {{Saba, Karim H. and Difilippo, Valeria and Kovac, Michal and Cornmark, Louise and Magnusson, Linda and Nilsson, Jenny and van den Bos, Hilda and Spierings, Diana C.J. and Bidgoli, Mahtab and Jonson, Tord and Sumathi, Vaiyapuri P. and Brosjö, Otte and Staaf, Johan and Foijer, Floris and Styring, Emelie and Nathrath, Michaela and Baumhoer, Daniel and Nord, Karolin H.}},
  issn         = {{0022-3417}},
  keywords     = {{gene fusion; osteosarcoma; p53; promoter swapping; separation-of-function mutation; TP53 intron 1; TP53 mutation; TP53 promoter; TP53 signalling pathway}},
  language     = {{eng}},
  pages        = {{147--160}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway}},
  url          = {{http://dx.doi.org/10.1002/path.6219}},
  doi          = {{10.1002/path.6219}},
  year         = {{2023}},
}