Transcriptome-wide association study of alternative polyadenylation identifies susceptibility genes in non-small cell lung cancer

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 NSCLC Chinese 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 a prognostic marker. 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'aQTLs 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 study (GWAS) for NSCLC involving 7035 cases and 185,413 cancer-free controls. We identified NSCLC-associated genes, highlighting TUBB, TEAD3, and PPP1R10. Combining the consistent results from colocalization analysis, differential APA analysis, and survival analysis, we provide novel evidence for the role TUBB 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 in East Asian populations.