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de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 Journal of Translational
DOI: 10.20517/jtgg.2021.32
Genetics and Genomics

Review Open Access

Genomic characterization of treatment-associated
small cell neuroendocrine carcinoma of the prostate

1
2
1
Ivan de Kouchkovsky , David A. Quigley , Eric J. Small , Rahul Aggarwal 1
1
Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
2
Department of Urology, University of California San Francisco, San Francisco, CA 94143, USA.
Correspondence to: Dr. Ivan de Kouchkovsky, Department of Medicine, University of California San Francisco, 550 16th Street,
Box 3211, San Francisco, CA 94158-3211, USA. E-mail: Ivan.deKouchkovsky@ucsf.edu
How to cite this article: de Kouchkovsky I, Quigley DA, Small EJ, Aggarwal R. Genomic characterization of treatment-associated
small cell neuroendocrine carcinoma of the prostate. J Transl Genet Genom 2021;5:265-77.
https://dx.doi.org/10.20517/jtgg.2021.32

Received: 11 Jun 2021 First Decision: 6 Jul 2021 Revised: 27 Jul 2021 Accepted: 3 Aug 2021 First online: 3 Aug 2021

Academic Editor: Sanjay Gupta Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate
cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC
is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of
prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by
the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased
canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53
mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical
differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart.
This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic
mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and
epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-
SCNC have contributed to improving the diagnosis and treatment of this aggressive disease.

Keywords: Castration-resistant prostate cancer, epigenetics, lineage plasticity, molecular genetics, neuroendocrine
prostate cancer, small cell carcinoma, prostate

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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