HSD3B1, prostate cancer mortality and modifiable outcomes

Area of Science:

• Oncology
• Genetics
• Endocrinology

Background:

• Androgen receptor (AR) signaling drives prostate cancer (PCa) progression.
• Androgen deprivation therapy (ADT) is a primary treatment, but castration-resistant PCa (CRPC) eventually develops.
• Germline variations can influence PCa progression and treatment response.

Purpose of the Study:

• To investigate the role of the HSD3B1 gene polymorphism in PCa progression and response to ADT.
• To explore the clinical implications of the HSD3B1 adrenal-permissive allele.
• To identify potential therapeutic targets for CRPC.

Main Methods:

• Analysis of clinical studies and large-scale datasets (e.g., Million Veteran Program).
• Association studies linking HSD3B1 genotype to PCa outcomes and mortality.
• Evaluation of mechanisms involving extra-gonadal androgen biosynthesis.

Main Results:

• The HSD3B1 adrenal-permissive allele enhances extra-gonadal androgen synthesis via 3β-hydroxysteroid dehydrogenase 1 (3βHSD1).
• Inheritance of this allele is associated with more rapid progression to CRPC and increased PCa-specific mortality.
• Adrenal androgen blockade can reverse negative effects, and the allele's frequency varies globally.

Conclusions:

• HSD3B1 germline testing can identify patients at higher risk for CRPC and mortality.
• Early, intensified AR-targeting interventions and adrenal androgen blockade are beneficial for carriers.
• Targeting 3βHSD1 offers a novel therapeutic strategy for advanced prostate cancer.