Genetic Regulation of Alternative Polyadenylation Provides Novel Insights into Molecular Mechanisms Underlying Non‐small Cell Lung Cancer

Emerging evidence emphasizes the critical role of alternative polyadenylation (APA) in posttranscriptional regulation of genes, and APA-associated genetic variants (apaQTLs) show particular relevance for multiple disease. However, genetic regulation of APA and its role in non-small cell lung cancer (NSCLC) risk have not been thoroughly studied. Here, by leveraging genotype and APA data from The Cancer Genome Atlas, the association between genetic variation and APA is determined in NSCLC samples. The identified apaQTLs are distinct from eQTLs and are preferentially enriched in functionally relevant characteristics, including poly(A) motifs, APA-associated RBP binding sites, functional elements, and known NSCLC risk loci. Moreover, genes associated with apaQTLs are broadly involved in cancer-related biological process. Of note, integration of apaQTL variants with traditional GWAS-derived PRS is proved as a potential screening tool for NSCLC. By integrating large-scale population and biological experiments, a functional apaQTL variant rs9606 in LYRM4 is identified. Mechanistically, rs9606 induces aberrant APA process of LYRM4 via allele-specific interacting with NUDT21, which lead to increased expression of oncogene LYRM4 and thus contribute to NSCLC risk. This study demonstrates the distinct contribution of APA-associated genetic variants in NSCLC risk, providing critical clues and potential targets for NSCLC etiology and clinical intervention.