Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals.
| Autor: | Kainov Y; Centre for Developmental Neurobiology, King's College London, London, United Kingdom.; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom., Hamid F; Centre for Developmental Neurobiology, King's College London, London, United Kingdom., Makeyev EV; Centre for Developmental Neurobiology, King's College London, London, United Kingdom. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2024 Dec 11; Vol. 13. Date of Electronic Publication: 2024 Dec 11. |
| DOI: | 10.7554/eLife.99040 |
| Abstrakt: | The expression of eukaryotic genes relies on the precise 3'-terminal cleavage and polyadenylation of newly synthesized pre-mRNA transcripts. Defects in these processes have been associated with various diseases, including cancer. While cancer-focused sequencing studies have identified numerous driver mutations in protein-coding sequences, noncoding drivers - particularly those affecting the cis-elements required for pre-mRNA cleavage and polyadenylation - have received less attention. Here, we systematically analysed somatic mutations affecting 3'UTR polyadenylation signals in human cancers using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset. We found a striking enrichment of cancer-specific somatic mutations that disrupt strong and evolutionarily conserved cleavage and polyadenylation signals within tumour suppressor genes. Further bioinformatics and experimental analyses conducted as a part of our study suggest that these mutations have a profound capacity to downregulate the expression of tumour suppressor genes. Thus, this work uncovers a novel class of noncoding somatic mutations with significant potential to drive cancer progression. Competing Interests: YK, FH, EM No competing interests declared (© 2024, Kainov et al.) |
| Databáze: | MEDLINE |
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