Abstract 4064: Transcriptome-Wide Association Study of Alternative Polyadenylation Identifies Susceptibility Genes in Non-Small Cell Lung Cancer

Abstract Alternative polyadenylation (APA) plays a crucial role in cancer development and prognosis. However, the molecular characteristics of APA related to non-small cell lung cancer (NSCLC) susceptibility remain understudied especially in East Asian populations. In this study, we constructed an atlas of APA-regulated 3' untranslated region (3'UTR) and profiled its genetic regulation in 747 lung tissue samples (including tumors and paired normal tissues) from 417 Chinese NSCLC patients. We verified a significant global shortening of 3'UTRs in tumor samples compared to normal samples and underscored the value of APA-regulation as prognostic markers. The 3'UTR APA quantitative trait loci (3'aQTL) was identified by regressing the percentage of distal poly(A) site usage index (PDUI) value on genetic variants. We found that a significant proportion 3'aQTL are independent of genetic regulation of expression and are specific in Chinese. We also conducted a 3'UTR APA transcriptome-wide association study (3'aTWAS) by integrating the APA regulation atlas with a genome-wide association studies (GWAS) for NSCLC involving 7, 035 cases and 185, 413 cancer-free controls. We identified NSCLC-associated genes. Combining the consistent results from colocalization analysis, differential APA analysis, and survival analysis, we provide novel evidence for the role APA regulation in NSCLC and identified potential upstream regulators. Overall, our study profiled the APA regulation and highlighted the substantial role of APA in NSCLC carcinogenesis and prognosis. Citation Format: Xiaohang Xu, Sicong Wang, Hanyi Zhou, Qilong Tan, Zeyong Lang, Yun Zhu, Huadi Yuan, Zixiang Wu, Ling Zhu, Kejia Hu, Wenyuan Li, Dan Zhou, Ming Wu, Xifeng Wu. Transcriptome-Wide Association Study of Alternative Polyadenylation Identifies Susceptibility Genes in Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4064.