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

Abstract

<div>AbstractPurpose:<p>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 biallelic <i>RB1</i> loss (RBS) that could be used to assess the clinical implications of <i>RB1</i> loss on a pan-cancer scale.</p>Experimental Design:<p>We utilized data from the Cancer Cell Line Encyclopedia (<i>N</i> = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic <i>RB1</i> loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (<i>N</i> = 11,007). RBS was then used to assess the clinical relevance of biallelic <i>RB1</i> loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.</p>Results:<p>RBS outperformed the leading existing signature for detecting <i>RB1</i> biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (<i>RB1</i> biallelic loss) was associated with promoter hypermethylation (<i>P</i> = 0.008) and gene body hypomethylation (<i>P</i> = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (<i>P</i> < 0.00001), overall (<i>P</i> = 0.0004), and disease-specific (<i>P</i> < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (<i>P</i> = 0.03) and of shorter overall survival in mCRPC (<i>P</i> = 0.004) independently of the number of DNA alterations in <i>RB1</i>.</p>Conclusions:<p>Our study provides the first validated tool to assess <i>RB1</i> biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.</p><p><i>See related commentary by Choudhury and Beltran, p. 4199</i></p></div>