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; Difilippo, Valeria; Kovac, Michal; Cornmark, Louise; Magnusson, Linda; Nilsson, Jenny; van den Bos, Hilda; Spierings, Diana Cj; Bidgoli, Mahtab; Jonson, Tord; Sumathi, Vaiyapuri P; Brosjö, Otte; Staaf, Johan; Foijer, Floris; Styring, Emelie; Nathrath, Michaela; Baumhoer, Daniel; Nord, Karolin H

doi:10.1002/path.6219

2024

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Titel:: Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway.
Dokumenttyp:: Journal Article; Research Support, Non-U.S. Gov't
Autor(en):: Saba, Karim H; Difilippo, Valeria; Kovac, Michal; Cornmark, Louise; Magnusson, Linda; Nilsson, Jenny; van den Bos, Hilda; Spierings, Diana Cj; Bidgoli, Mahtab; Jonson, Tord; Sumathi, Vaiyapuri P; Brosjö, Otte; Staaf, Johan; Foijer, Floris; Styring, Emelie; Nathrath, Michaela; Baumhoer, Daniel; Nord, Karolin H
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 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.
Zeitschriftentitel:: J Pathol
Jahr:: 2024
Band / Volume:: 262
Heft / Issue:: 2
Seitenangaben Beitrag:: 147-160
Volltext / DOI:: doi:10.1002/path.6219
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/38010733
Print-ISSN:: 0022-3417
TUM Einrichtung:: Klinik und Poliklinik für Kinder- und Jugendmedizin (Prof. Hauer)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Kinder- und Jugendmedizin (Prof. Hauer)2024