Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types

Abstract

Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting bi-allelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale. We utilized data from the Cancer Cell Line Encyclopedia (N=995) to develop the first pan-cancer transcriptomic signature for predicting bi-allelic RB1 loss (RBS). Model accuracy was validated using the TCGA Pan-Cancer dataset (N=11,007). RBS was then used to assess the clinical relevance of bi-allelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort. RBS outperformed the leading existing signature for detecting RB1 bi-allelic loss across all cancer types in TCGA Pan-Cancer (AUC: 0.89 vs. 0.66). High RBS ( RB1 bi-allelic loss) was associated with promoter hypermethylation ( P =0.008) and gene body hypomethylation ( P =0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free ( P <0.00001), overall ( P =0.0004), and disease-specific ( P <0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer ( P =0.03) and of shorter overall survival in mCRPC ( P =0.004) independently of the number of DNA alterations in RB1 . Our study provides the first validated tool to assess RB1 bi-allelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-seq results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.