HSD3B1 1245C: A Risk Allele for Resistance to Androgen Deprivation Therapy (ADT)
Introduction
Advancements in genetic testing have paved the way for personalized medicine, particularly in the field of oncology. One notable gene variant, HSD3B1 1245C, has emerged as a risk allele associated with resistance to androgen deprivation therapy (ADT) in prostate cancer patients. This variant, included in the ProstateNow germline panel, has significant clinical implications and may guide treatment decisions for individuals with localized prostate cancer. In this blog post, we explore the characteristics of the HSD3B1 1245C allele and its role in mediating ADT resistance.
Understanding HSD3B1 1245C
The frequency of the HSD3B1 1245C allele varies among different ancestral populations, with Europeans having the highest frequency at 34%, followed by Americans (20%), South Asians (16%), Africans (9%), and East Asians (8%). Initially identified as a prostate cancer risk-associated single nucleotide polymorphism (SNP) used in the calculation of ProstateNow’s genetic risk score (GRS), the HSD3B1 1245C variant is now recognized as a standalone variant due to its clinical relevance.
Clinical Impact
Studies have shown that patients carrying the HSD3B1 1245C risk allele display increased resistance to ADT, shorter time to the development of castration resistance, and worse clinical outcomes after hormonal therapy compared to those with the wildtype allele. This effect is even more pronounced in individuals who are homozygous for the risk allele. Due to the added risk of future treatment failure, identifying patients with localized prostate cancer who carry this risk allele can supplement traditional clinical variables in determining appropriate treatment strategies.
Mechanism of ADT Resistance
The HSD3B1 gene encodes an enzyme called 3β-HSD1, which plays a vital role in the synthesis of extragonadal androgens. Specifically, 3β-HSD1 catalyzes a rate-limiting step in the conversion of adrenal androgen precursor steroids into potent androgens such as testosterone and dihydrotestosterone (DHT).
Androgen deprivation therapy (ADT) works by blocking the production of testicular androgens, which in turn inhibits tumor growth by reducing stimulation of intratumoral androgen receptors. However, resistance to ADT develops as mechanisms arise to overcome this blockade, often through increased extragonadal androgen production. Compared to the wildtype allele, the HSD3B1 1245C risk allele encodes an enzyme with increased resistance to ubiquitination and degradation, allowing for enhanced conversion of precursor steroids into androgens. Consequently, the accumulation of these adrenal-derived androgens within the prostate can stimulate the androgen receptor and promote prostate tumor growth in the absence of testicular-derived testosterone.
Conclusion
The HSD3B1 1245C allele serves as a significant biomarker for ADT resistance in prostate cancer patients. By identifying individuals with this risk allele through genetic testing, healthcare providers can make informed decisions regarding treatment options. Patients carrying the HSD3B1 1245C risk allele may benefit from earlier escalation of therapy due to their increased susceptibility to ADT treatment failure. Integrating genetic information, such as HSD3B1 genotyping, with traditional clinical variables empowers clinicians to offer personalized, tailored treatment approaches for patients with localized prostate cancer.
References:
Sabharwal N, Sharifi N. HSD3B1 Genotypes conferring adrenal-restrictive and adrenal-permissive phenotypes in prostate cancer and beyond. Endocrinology. 2019;160(9):2180-2188. doi10.1210/en.2019-00366
Hettel, D., Sharifi, N. HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer. Nat Rev Urol. 2018;15(3):191-196. doi:10.1038/nrurol.2017.201
Hearn JWD, AbuAli G, Reichard CA, et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multi cohort study. Lancet Oncol. 2016;17(10):1435-1444. doi:10.10016/S1470-2045(16)30227-3
Hearn JWD, Sweeney CJ, Almassi N, et al. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncol. 2020;6(4):e196496. doi:10.1001/jamaoncol.2019.6496