Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma
Open Access
- 24 May 2019
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 145 (12), 3453-3461
- https://doi.org/10.1002/ijc.32430
Abstract
Prostatic small cell neuroendocrine carcinoma (SC/NE) is well studied in metastatic CRPC, however, it is not well characterized in the primary setting. Herein, we used gene expression profiling of SC/NE PCa to develop a 212 gene signature to identify treatment‐naïve primary prostatic tumors that are molecularly analogous to SC/NE (SC/NE‐like PCa) .. The 212 gene signature was tested in several cohorts confirming similar molecular profile between prostatic SC/NE and small cell lung carcinoma. The signature was then translated into a genomic score (SCGScore) using modularized logistic regression modelling and validated in four independent cohorts achieving an average AUC >0.95. The signature was evaluated in more than 25,000 primary adenocarcinoma to characterize the biology, prognosis and potential therapeutic response of predicted SC/NE‐like tumors. Assessing SCGScore in a prospective cohort of 17,967 RP and 6,697 biopsy treatment‐ naïve primary tumors from the Decipher GRID registry, approximately 1% of the patients were found to have a SC/NE‐like transcriptional profile, where 0.5% and 3 % of GG1 and GG5 patients respectively showed to be SC/NE‐like. More than 80% of these patients are genomically high‐risk based on Decipher score. Interrogating in vitro drug sensitivity analyses, SC/NE‐like prostatic tumors showed higher response to PARP and HDAC inhibitors.Keywords
Funding Information
- Prostate Cancer Canada
- Movember Foundation (B2013‐01)
This publication has 17 references indexed in Scilit:
- Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk MenEuropean Urology, 2016
- The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate CancerCell Reports, 2015
- Re: Steven Joniau, Alberto Briganti, Paolo Gontero, et al. Stratification of High-risk Prostate Cancer into Prognostic Categories: A European Multi-institutional Study. Eur Urol 2015;67:157–64European Urology, 2015
- PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancerScientific Reports, 2013
- A single-sample microarray normalization method to facilitate personalized-medicine workflowsGenomics, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate CancerJournal of Clinical Oncology, 2011
- Integrative Genomic Profiling of Human Prostate CancerCancer Cell, 2010
- ConsensusClusterPlus: a class discovery tool with confidence assessments and item trackingBioinformatics, 2010
- Adjusting batch effects in microarray expression data using empirical Bayes methodsBiostatistics, 2006