Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: The HSD3B1 gene encodes the enzyme 3ß-hydroxysteroid dehydrogenase-1 (3ßHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. METHODS: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. RESULTS: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. CONCLUSION: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.

Examination of ELN as a candidate gene in the Utah intracranial aneurysm pedigrees.

BACKGROUND AND PURPOSE: A study of intracranial aneurysm (IA) sibpairs suggested association of an ELN haplotype with IA risk. Subsequent linkage analysis of the ELN region on chromosome 7q11 in high-risk Utah IA pedigrees significantly confirmed linkage between IA and the ELN region. METHODS: We have investigated the ELN gene as a potential candidate gene for IA in Utah pedigrees. One IA case from each pedigree, who shared an ELN region haplotype segregating in the pedigree, was screened for mutation. The promoter region, 34 exons, and the 3'UTR (UnTranslated Region) of the ELN gene were screened for variants using DHPLC. RESULTS: Variants were observed in the promoter region, exons 4 and 6, and the 3'UTR. Variants in exon 6 and in one 3'UTR position were unique to Utah. The remaining variants were absent in the controls. There was no evidence for segregation of the ELN variants found in IA cases with the hypothesized chromosome 7 haplotypes segregating in pedigrees. CONCLUSIONS: Our analysis does not support ELN as the gene responsible for familial IA in the linked Utah IA pedigrees.