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. 2024 Aug 15;84(16):2707-2719.
doi: 10.1158/0008-5472.CAN-24-0521.

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Xingyi Guo  1   2 , Jie Ping  1 , Yaohua Yang  3   4 , Xinwan Su  5 , Xiao-Ou Shu  1 , Wanqing Wen  1 , Zhishan Chen  1 , Yunjing Zhang  5 , Ran Tao  6 , Guochong Jia  1 , Jingni He  7   8 , Qiuyin Cai  1 , Qingrun Zhang  9 , Graham G Giles  10 , Rachel Pearlman  11 , Gad Rennert  12 , Pavel Vodicka  13   14   15 , Amanda Phipps  16   17 , Stephen B Gruber  18 , Graham Casey  3 , Ulrike Peters  16   17 , Jirong Long  1 , Weiqiang Lin  5 , Wei Zheng  1
Affiliations

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Xingyi Guo et al. Cancer Res. .

Abstract

Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3'-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3'-UTR variants demonstrated that the risk alleles of 3'-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3'UTRs to genetic susceptibility to cancer.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: The authors declare no competing interests.

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