Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway.
TP53 intron 1
TP53 mutation
TP53 promoter
TP53 signalling pathway
gene fusion
osteosarcoma
p53
promoter swapping
separation-of-function mutation
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
revised:
24
08
2023
received:
24
04
2023
accepted:
19
09
2023
medline:
27
11
2023
pubmed:
27
11
2023
entrez:
27
11
2023
Statut:
aheadofprint
Résumé
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. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Swiss National Science Foundation
Pays : Switzerland
Informations de copyright
© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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