A common genetic variation in the HSD3B1 gene, known as the adrenal-permissive allele, plays a significant role in prostate cancer progression and response to treatment. This allele leads to increased activity of the 3βHSD1 enzyme, which is responsible for producing androgens (male hormones) in the adrenal glands.

In men with the adrenal-permissive allele, androgen deprivation therapy (ADT) is less effective because their bodies continue to produce androgens even after the testicles are removed. This can lead to the development of castration-resistant prostate cancer, a more aggressive form of the disease.

Clinical studies have shown that men who inherit the adrenal-permissive allele experience faster progression to castration-resistant prostate cancer and have a higher mortality rate. However, this negative impact can be mitigated by blocking adrenal androgen production upfront.

The frequency of the adrenal-permissive allele varies across different populations, which may contribute to differences in clinical outcomes among these groups. Large-scale studies have confirmed that inheriting two copies of this allele is an independent risk factor for prostate cancer-specific mortality.

These findings highlight the importance of integrating HSD3B1 testing into clinical practice. Genetic testing can identify men who are at higher risk of developing aggressive prostate cancer and may benefit from early and intensified androgen-targeting therapies. Additionally, 3βHSD1 is a promising target for drug development, offering new strategies for systemic prostate cancer treatment.

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