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

TY - JOUR

T1 - Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals

AU - Kainov, Yaroslav

AU - Hamid, Fursham

AU - Makeyev, Eugene

PY - 2024/12/11

Y1 - 2024/12/11

N2 - 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 3’UTR 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.

AB - 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 3’UTR 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.

U2 - 10.7554/eLife.99040

DO - 10.7554/eLife.99040

M3 - Article

SN - 2050-084X

VL - 13

JO - eLife

JF - eLife

M1 - RP99040

ER -