| Autor: |
Karim H. Saba, Valeria Difilippo, Michal Kovac, Louise Cornmark, Linda Magnusson, Jenny Nilsson, Hilda van den Bos, Diana C. J. Spierings, Mahtab Bidgoli, Tord Jonson, Vaiyapuri P. Sumathi, Otte Brosjö, Johan Staaf, Floris Foijer, Emelie Styring, Michaela Nathrath, Daniel Baumhoer, Karolin H. Nord |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
How massive genome rearrangements confer a competitive advantage to a cancer cell has remained an enigma. The malignant bone tumour osteosarcoma harbours an extreme number of structural variations and thereby holds the key to understand complex cancer genomes. Genome integrity in osteosarcoma is generally lost together with disruption of normalTP53gene function, the latter commonly through either missense mutations or structural alterations that separate the promoter region from the coding parts of the gene. To unravel the consequences of aTP53promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show thatTP53structural variations are early events that not only facilitate further chromosomal alterations, but also allow theTP53promoter to upregulate genes erroneously placed under its control. Paradoxically, many of the induced genes are part of theTP53-associated transcriptome, suggesting a need to counterbalance loss ofTP53function through ‘separation-of-function’ mutations via promoter swapping. Our findings demonstrate how massive genome errors can functionally turn the promoter region of a tumour suppressor gene into a constitutively active oncogenic driver. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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