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bioRxiv · 10.1101/2024.06.23.600297

Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals

Kainov, Y.·Hamid, F.·Makeyev, E. V.
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Abstract

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 cancer somatic mutations affecting 3UTR polyadenylation signals 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.

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Kainov, Y., Hamid, F., Makeyev, E. V.. 2024-06-28. Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals. https://doi.org/10.1101/2024.06.23.600297

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