Genetic-informed alternative RNA splicing serves an essential role in carcinogenesis and prognosis of non-small-cell lung cancer

Dysregulated RNA splicing is a post-transcriptional molecular feature that significantly influences tumor progression and prognosis. However, the role of alternative splicing in the development of non-small cell lung cancer (NSCLC) within the Chinese population remains poorly understood. In this study, we investigated the genetic regulation of splicing in 245 tumor and 297 normal lung tissue samples from Chinese NSCLC patients. By integrating splicing data with a meta-analyzed genome-wide association study (GWAS) for NSCLC in East Asians (7,035 cases and 185,413 controls), we identified 14 novel NSCLC-associated splicing events (FDR < 0.05) through a splicing transcriptome-wide association study (spTWAS). Additionally, we validated the involvement of the splicing gene FARP1 and the EIF3 family, both of which have been associated with NSCLC risk. By combining the results of differential splicing analysis and spTWAS, followed by colocalization analysis and putative splicing factor predictions, we highlighted the critical roles of splicing events in TP63 (1st exon skipping) and TPM1 (6th exons mutually exclusive) in NSCLC, bridging the missing biology between SNP-NSCLC association. Furthermore, we underscored several splicing events in genes including ILK, which were also associated with NSCLC prognosis. In conclusion, this study elucidated the genetic architecture of splicing in lung tissues and revealed the significant contribution of splicing dysregulation to the carcinogenesis and prognosis of NSCLC.