Abstract 545: Prognostic alternative mRNA splicing signature in non-small cell lung cancer

Abstract

Abstract Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. However, alternative splicing in non-small cell lung cancer (NSCLC) is largely unstudied. In this study, seven types of alternative splicing were profiled in 491 lung adenocarcinoma (LUAD) and 471 lung squamous cell carcinoma (LUSC) patients in TCGA using RNA sequencing data. Prognostic predictors for LUAD, LUSC and merged NSCLC patients were built by integrated survival analysis. Gene network and splicing correlation network analyses were also conducted. Overall, we detected 45,062 and 50,732 alternative splicing events in LUAD and LUSC, respectively, almost half of them were exon skipping events. A total of 3,691 and 2,403 alternative splicing events were significantly associated with patient survival in LUAD and LUSC, respectively. Gene network analysis uncovered important hub genes or nodes such as EGFR, CD44, PIK3C3, RRAS2, MAPKAP1 and FGFR2. The area under the curve (AUC) of the receiver-operator characteristic (ROC) curve for prognostic predictors in LUAD and LUSC were 0.960 and 0.940 at 2000 days of overall survival. Most relevant for clinical application, we also built the prognostic predictor for NSCLC patients with high performance. The AUC of ROC curve in NSCLC was 0.817 which were also over 0.8 in LUAD and LUSC, separately. Moreover, expression of 49 and 9 survival associated splicing factors were significantly correlated with 75 survival associated alternative splicing events in LUAD and LUSC, respectively. Interestingly, splicing correlation networks uncovered that “oncogenic“ splicing factors were up-regulated in LUAD while “tumor suppressor” splicing factors were down-regulated in LUSC. Survival associated splice factors might have opposite roles in the regulation of RNA splicing in LUAD and LUSC. In conclusion, we created prognostic predictors based on alternative splicing events with high performances for risk stratification in NSCLC patients and uncovered interesting splicing networks in LUAD and LUSC which could be underlying mechanisms. Citation Format: Yuan Li, Nan Sun, Zhiliang Lu, Shouguo Sun, Jianbing Huang, Zhaoli Chen, Jie He. Prognostic alternative mRNA splicing signature in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 545. doi:10.1158/1538-7445.AM2017-545