TY - JOUR
T1 - Novel Rb1-loss transcriptomic signature is associated with poor clinical outcomes across cancer types
AU - Chen, William S.
AU - Alshalalfa, Mohammed
AU - Zhao, Shuang G.
AU - Liu, Yang
AU - Mahal, Brandon A.
AU - Quigley, David A.
AU - Wei, Ting
AU - Davicioni, Elai
AU - Rebbeck, Timothy R.
AU - Kantoff, Philip W.
AU - Maher, Christopher A.
AU - Knudsen, Karen E.
AU - Small, Eric J.
AU - Nguyen, Paul L.
AU - Feng, Felix Y.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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 ¼ 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 ¼ 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 ¼ 0.008) and gene body hypomethylation (P ¼ 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 ¼ 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 ¼ 0.03) and of shorter overall survival in mCRPC (P ¼ 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.
AB - 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 ¼ 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 ¼ 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 ¼ 0.008) and gene body hypomethylation (P ¼ 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 ¼ 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 ¼ 0.03) and of shorter overall survival in mCRPC (P ¼ 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.
UR - http://www.scopus.com/inward/record.url?scp=85068974728&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0404
DO - 10.1158/1078-0432.CCR-19-0404
M3 - Article
C2 - 31010837
AN - SCOPUS:85068974728
SN - 1078-0432
VL - 25
SP - 4290
EP - 4299
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -