Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes

遗传学 生物 三素数非翻译区 基因 聚腺苷酸 前列腺癌 基因型 癌症 等位基因 遗传关联 非翻译区 单核苷酸多态性 信使核糖核酸 基因表达
作者
Xingyi Guo,Jie Ping,Yaohua Yang,Xinwan Su,Xiao‐Ou Shu,Wanqing Wen,Zhishan Chen,Yunjing Zhang,Ran Tao,Guochong Jia,Jingni He,Qiuyin Cai,Qingrun Zhang,Graham G. Giles,Rachel Pearlman,Gad Rennert,Pavel Vodička,Amanda I. Phipps,Stephen B. Gruber,Graham Casey,Ulrike Peters,Jirong Long,Weiqiang Lin,Wei Zheng
出处
期刊:Cancer Research [American Association for Cancer Research]
被引量:1
标识
DOI:10.1158/0008-5472.can-24-0521
摘要

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. Herein, we conducted large alternative polyadenylation-wide association studies (APA-WAS) to investigate associations of APA levels with 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, including breast, ovary, prostate, colorectum, lung, and pancreas. 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 co-localization 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 post-transcriptional activities of their target genes compared to 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.
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