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.

中文翻译：

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大规模替代多腺苷酸化关联研究以确定假定的癌症易感基因


替代多腺苷酸化 (APA) 调节 3' 非翻译区 (3' UTR) 的 mRNA 加工，影响 mRNA 稳定性和翻译效率。对基因调控 APA 的研究有可能为癌症风险提供深入见解。在此，我们进行了大型替代多腺苷酸化范围关联研究 (APA-WAS)，以调查 APA 水平与癌症风险的关联。使用来自基因型组织表达项目的 1,337 个样本的基因型和 RNA 测序数据建立遗传模型来预测多个组织中的 APA 水平。通过将预测模型应用于欧洲血统人群中六种常见癌症（包括乳腺癌、卵巢癌、前列腺癌、结直肠癌、肺癌和胰腺癌）的大型全基因组关联研究的数据，评估了基因预测的 APA 水平与癌症风险的关联。总共 58 个风险基因（对应 76 个 APA 位点）与至少一种癌症相关，其中包括 25 个以前与癌症易感性无关的基因。在已确定的风险 APA 中，97.4% 和 26.3% 分别得到 3' UTR APA 数量性状基因座和共定位分析的支持。对四种选定的假定调节性 3' UTR 变体的荧光素酶报告基因检测表明，3' UTR 变体的风险等位基因 rs324015 (STAT6)、rs2280503 (DIP2B)、rs1128450 (FBXO38) 和 rs145220637 (LDHA) 显着增加了转录后与参考等位基因相比，其目标基因的活性。此外，靶基因的敲除证实了它们促进增殖和迁移的能力。总的来说，这项研究深入了解了 APA 在常见癌症遗传易感性中的作用。