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- Title
Adrenal-Permissive Germline HSD3B1 Allele and Prostate Cancer Outcomes.
- Authors
McKay, Rana R.; Nelson, Tyler J.; Pagadala, Meghana S.; Teerlink, Craig C.; Gao, Anthony; Bryant, Alex K.; Agiri, Fatai Y.; Guram, Kripa; Thompson, Reid F.; Pridgen, Kathryn M.; Seibert, Tyler M.; Lee, Kyung Min; Carter, Hannah; Lynch, Julie A.; Hauger, Richard L.; Rose, Brent S.
- Abstract
This cohort study analyzes the association of HSD3B1 status with prostate cancer outcomes among patients in the Veterans Affairs Health System in the US. Key Points: Question: Is the adrenal-permissive HSD3B1 homozygous genotype associated with worse clinical outcomes in men with prostate cancer? Findings: In this cohort study of 5287 men with prostate cancer in the Million Veteran Program, the HSD3B1 adrenal-permissive homozygous genotype (compared with the adrenal-restrictive homozygous and heterozygous genotype) was associated with worse prostate cancer–specific mortality. Subset analysis of metastatic prostate cancer also showed worse prostate cancer–specific mortality in the adrenal-permissive homozygous genotype group. Meaning: These findings suggest that the HSD3B1 adrenal-permissive homozygous genotype is associated with inferior outcomes in men with prostate cancer. Importance: The adrenal androgen–metabolizing 3β-hydroxysteroid dehydrogenase-1 enzyme, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary for synthesizing nontesticular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding the 3β-HSD1 protein with decreased susceptibility to degradation resulting in higher extragonadal androgen synthesis. Retrospective studies have suggested an association of the HSD3B1 adrenal-permissive homozygous genotype with androgen deprivation therapy resistance in prostate cancer. Objective: To evaluate differences in mortality outcomes by HSD3B1 genetic status among men with prostate cancer. Design, Setting, and Participants: This cohort study of patients with prostate cancer who were enrolled in the Million Veteran Program within the Veterans Health Administration (VHA) system between 2011 and 2023 collected genotyping and phenotyping information. Exposure: HSD3B1 genotype status was categorized as AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), or CC (homozygous adrenal-permissive). Main Outcomes and Measures: The primary outcome of this study was prostate cancer–specific mortality (PCSM), defined as the time from diagnosis to death from prostate cancer, censored at the date of last VHA follow-up. Secondary outcomes included incidence of metastases and PCSM in predefined subgroups. Results: Of the 5287 participants (median [IQR] age, 69 [64-74] years), 402 (7.6%) had the CC genotype, 1970 (37.3%) had the AC genotype, and 2915 (55.1%) had the AA genotype. Overall, the primary cause of death for 91 patients (1.7%) was prostate cancer. Cumulative incidence of PCSM at 5 years after prostate cancer diagnosis was higher among men with the CC genotype (4.0%; 95% CI, 1.7%-6.2%) compared with the AC genotype (2.1%; 95% CI, 1.3%-2.8%) and AA genotype (1.9%; 95% CI, 1.3%-2.4%) (P =.02). In the 619 patients who developed metastatic disease at any time, the cumulative incidence of PCSM at 5 years was higher among patients with the CC genotype (36.0%; 95% CI, 16.7%-50.8%) compared with the AC genotype (17.9%; 95% CI, 10.5%-24.7%) and AA genotype (18.5%; 95% CI, 12.0%-24.6%) (P =.01). Conclusions and Relevance: In this cohort study of US veterans undergoing treatment for prostate cancer at the VHA, the HSD3B1 CC genotype was associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis.
- Subjects
UTAH; GERM cells; RESEARCH funding; PROSTATE tumors; TUMOR markers; DESCRIPTIVE statistics; RETROSPECTIVE studies; CHI-squared test; MULTIVARIATE analysis; LONGITUDINAL method; METASTASIS; OXIDOREDUCTASES; CONFIDENCE intervals; SURVIVAL analysis (Biometry); ALLELES; GENETICS; GENOTYPES
- Publication
JAMA Network Open, 2024, Vol 7, Issue 3, pe242976
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2024.2976