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Germline HSD3B1 Genetics and Prostate Cancer Outcomes.

By: Lewis Thomas, Nima Sharifi

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195.
2020-07-06; doi: 10.1016/j.urology.2020.08.028

Abstract

Dihydrotestosterone synthesis in prostate cancer from adrenal DHEA/DHEA-sulfate requires enzymatic conversion in tumor tissues. 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1) is an absolutely necessary enzyme for such dihydrotestosterone synthesis and is encoded by the gene HSD3B1 which comes in two functional inherited forms described in 2013. The adrenal-permissive HSD3B1(1245C) allele allows for rapid dihydrotestosterone synthesis. The adrenal-restrictive HSD3B1(1245A) allele limits androgen synthesis. Studies from multiple cohorts show that adrenal-permissive allele inheritance confers worse outcomes and shorter survival after castration in low-volume prostate cancer and poor outcomes after abiraterone or enzalutamide treatment for castration-resistant prostate cancer. Here, we review the clinical data and implications.