The mutation in splicing factor genes correlates with unfavorable prognosis, genomic instability, anti-tumor immunosuppression and increased immunotherapy response in pan-cancer.

Abstract

Splicing abnormality resulting from somatic mutations in key splicing factor genes (SFG) has been detected in various cancers. Hence, an in-depth study of splicing factor genes mutations' impact on pan-cancer is meaningful. This study investigated associations of splicing factor genes mutations with clinical features, tumor progression phenotypes, genomic integrity, anti-tumor immune responses, and immunotherapy response in 12 common cancer types from the TCGA database. Compared to SFG-wildtype cancers, SFG-mutated cancers displayed worse survival prognosis, higher tumor mutation burden and aneuploidy levels, higher expression of immunosuppressive signatures, and higher levels of tumor stemness, proliferation potential, and intratumor heterogeneity (ITH). However, splicing factor genes-mutated cancers showed higher response rates to immune checkpoint inhibitors than splicing factor genes-wildtype cancers in six cancer cohorts. Single-cell data analysis confirmed that splicing factor genes mutations were associated with increased tumor stemness, proliferation capacity, PD-L1 expression, intratumor heterogeneity, and aneuploidy levels. Our data suggest that the mutation in key splicing factor genes correlates with unfavorable clinical outcomes and disease progression, genomic instability, anti-tumor immunosuppression, and increased immunotherapy response in pan-cancer. Thus, the splicing factor genes mutation is an adverse prognostic factor and a positive marker for immunotherapy response in cancer.