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.

Cancer Epidemiology Division Cancer Council Victoria Melbourne Australia

Center for Public Health Genomics University of Virginia Charlottesville Virginia

Department of Biochemistry and Molecular Biology University of Calgary Calgary Canada

Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville Tennessee

Department of Biostatistics Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville Tennessee

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Epidemiology University of Washington School of Public Health Seattle Washington

Department of Mathematics and Statistics Alberta Children's Hospital Research Institute Arnie Charbonneau Cancer Institute University of Calgary Calgary Canada

Department of Medical Genetics University of Calgary Calgary Canada

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Preventive Medicine and USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles California

Department of Public Health Sciences UVA Comprehensive Cancer Center School of Medicine University of Virginia Charlottesville Virginia

Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville Tennessee

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus Ohio

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

International Institutes of Medicine the 4th Affiliated Hospital of School of Medicine and International School of Medicine Zhejiang University Yiwu China

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

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medRxiv. 2023 Nov 07:2023.11.05.23298125. doi: 10.1101/2023.11.05.23298125. PubMed

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