Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Cancer Res. 2024 Aug 15;84(16):2707-2719. doi: 10.1158/0008-5472.CAN-24-0521.
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.
可变多聚腺苷酸化 (APA) 调节 3' 非翻译区 (3'UTR) 中的 mRNA 加工，影响 mRNA 的稳定性和翻译效率。对遗传调控 APA 的研究有可能深入了解癌症风险。在这项研究中，我们进行了广泛的 APA 全关联研究，以研究 APA 水平与癌症风险之间的关联。使用来自 1337 个来自基因-组织表达项目的样本的基因型和 RNA 测序数据，构建了遗传模型来预测多种组织中的 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（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数据，评估了遗传预测的 APA 水平与癌症风险的关联。总共确定了 58 个与至少一种癌症相关的风险基因（对应 76 个 APA 位点），包括 25 个先前与癌症易感性无关的基因。在所确定的风险 APAs 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。对四个选定的假定调节 3'-UTR 变体的荧光素酶报告基因检测表明，与参考等位基因相比，3'-UTR 变体 rs324015（STAT6）、rs2280503（DIP2B）、rs1128450（FBXO38）和 rs145220637（LDHA）的风险等位基因显著增加了其靶基因的转录后活性。此外，靶基因的敲低证实了它们促进增殖和迁移的能力。总体而言，这项研究提供了 APA 在常见癌症遗传易感性中的作用的见解。意义：系统评估 APA 与癌症风险的关联揭示了 58 个潜在的易感基因，突出了遗传调控 3'UTR 的 APA 对癌症遗传易感性的贡献。
