Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma

Mohammed Alshalalfa, Yang Liu, Alexander W. Wyatt, Ewan A. Gibb, Harrison K. Tsai, Nicholas Erho, Jonathan Lehrer, Mandeep Takhar, Varune R. Ramnarine, Colin C. Collins, Robert B. Den, Edward M. Schaeffer, Elai Davicioni, Tamara L. Lotan, Tarek A. Bismar

Research output: Contribution to journalArticlepeer-review

Abstract

Prostatic small cell neuroendocrine carcinoma (SC/NE) is well studied in metastatic castration-resistant prostate cancer; however, it is not well characterized in the primary setting. Herein, we used gene expression profiling of SC/NE prostate cancer (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 modeling and validated in four independent cohorts achieving an average AUC >0.95. The signature was evaluated in more than 25,000 primary adenocarcinomas 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 Genomic Resource Information Database registry, approximately 1% of the patients were found to have a SC/NE-like transcriptional profile, whereas 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.

Original languageEnglish (US)
Pages (from-to)3453-3461
Number of pages9
JournalInternational Journal of Cancer
Volume145
Issue number12
DOIs
StatePublished - Dec 15 2019

Keywords

  • SC/NE-like
  • drug sensitivity
  • localized
  • molecular signature
  • neuroendocrine prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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