Abstract 4439: Genetic alterations in specific RNA processing genes is associated with poor patient outcome in prostate cancer

Abstract

Abstract Altered expression of splicing factors has been implicated in human cancers but their role in disease progression is complex due to the magnitude of potential protein products. We previously showed that androgen withdrawal led to increased alternatively spliced products in mouse Pten-deficient prostate tumors. Here, we perform gene expression analysis this mouse prostate cancer model to identify candidate mRNA processing genes implicated in the progression to castration-resistant disease. Genome-wide analysis revealed a set of 43 unique RNA processing and splicing factor genes associated with the progression to castration-resistant disease. Expression analysis of this gene set was examined in a pan-cancer analysis of 30 TCGA cancer studies covering 26 human cancer types. Alterations of this gene set (z-score threshold variances >2) were found in 70.5% (6978/9896) of cases. The median percentage of affected cases across the studies ranged from 28.2-98.2% with a median of 78.3%. In prostate cancer patients (TCGA-Prostate Adenocarcinoma (PRAD)), 65.7% (327/497) of the cases had mRNA alterations of this gene set. Twenty-seven of the 30 studies had survival data, of these only three studies indicated poor disease-free survival (DSF) outcomes with mRNA alterations: TCGA-PRAD, P=0.00616; TCGA-Brain Lower Grade Glioma (BLGG), P=0.0088; TCGA-Thymoma, P=0.0265. In the TCGA-PRAD study, the median time to DSF was 81.2 months in altered cases vs. median not reached in non-altered cases. In three studies, favorable outcomes were seen in cases with alterations in the gene set: TCGA-Uveal melanoma, TCGA- Glioblastoma Multiforme and TCGA-Lung Squamous Cell Carcinoma. TCGA-BLGG was the only study to show a statistically significant association between gene set alterations and overall survival (OS), P=0.0206. In TCGA-PRAD, median OS was 115 months in altered cases vs. median not reached in non-altered cases P=0.262. We further analyzed the scope of molecular alterations of this gene set in prostate cancer patients, overall, 78.9% (393/498) of the cases had gene alterations consisting of mutations, amplifications, deletions, and mRNA downregulation in six (1.2%), two (0.4%), 49 (9.8%), 193 (38.8%), and 143 (28.7%) cases, respectively. Notably a strong association was revealed for poor OS for cases with mutations/copy number alterations (P=0.00621). These data suggest that molecular alterations in specific RNA processing genes can cooperate to promote specific cancer types and further studies will be required to fully understand the prostate cancer-driving events in this gene set. Citation Format: Koichi Sugimoto, Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Genetic alterations in specific RNA processing genes is associated with poor patient outcome in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4439.