Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Pharmacogenomics J. 2021 Aug;21(4):440-445. doi: 10.1038/s41397-021-00220-0. Epub 2021 Mar 1.
Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.
HSD3B1 基因（编码 3β-羟类固醇脱氢酶-1）中的错义多态性与阿比特龙治疗后的结局相关。其他雄激素代谢酶可能参与阿比特龙的治疗效果。在这项研究中，我们研究了雄激素和阿比特龙代谢相关基因多态性在接受阿比特龙治疗的前列腺癌患者中的意义。共纳入 2014 年至 2018 年间接受阿比特龙治疗的 99 例日本男性去势抵抗性前列腺癌患者。从全血样本中提取基因组 DNA，并通过基于 PCR 的技术对 SRD5A2（rs523349）、CYP17A1（rs743572）、CYP17A1（rs2486758）和 AKR1C3（rs12529）进行基因分型。在 99 例患者中，分别有 32 例（32.3%）、49 例（49.5%）和 18 例（18.2%）携带 SRD5A2 的 GG、GC 和 CC 等位基因。多因素分析显示，与 GG/GC 等位基因相比，CC 等位基因与治疗失败风险降低相关（危险比，0.43；95%置信区间，0.20-0.87；P=0.017）。在使用 HSD3B1 和 SRD5A2 多态性的组合模型中，与 HSD3B1 中的 AA 和 SRD5A2 中的 GG/GC 的组合相比，其他组合与治疗失败风险降低相关（危险比，0.34；95%置信区间，0.17-0.62；P=0.0003）。本研究表明，SRD5A2 遗传变异与阿比特龙治疗失败风险相关。HSD3B1 与 SRD5A2 遗传变异的联合使用增强了预后分层的能力。
