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Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 25(14)
- Publication Year :
- 2019
-
Abstract
- Purpose: 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 RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale. Experimental Design: We utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort. Results: RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic 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. Conclusions: Our study provides the first validated tool to assess RB1 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. See related commentary by Choudhury and Beltran, p. 4199
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Computational biology
Biology
Article
Transcriptome
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Promoter hypermethylation
Cancer genome
Neoplasms
medicine
Biomarkers, Tumor
Gene silencing
Humans
Clinical significance
Epigenetics
Cancer cell line encyclopedia
medicine.disease
Prognosis
eye diseases
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Disease Progression
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 25
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....12c95da2f4a9b2e08fe599d8c97a247f