The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer
The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer
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DOI：
10.1038/s41397-021-00220-0
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发表时间：
2021-03-01
影响因子：
2.8
通讯作者：
Eto, Masatoshi
中科院分区：
文献类型：
--
作者：
Shiota, Masaki;Akamatsu, Shusuke;Eto, Masatoshi
编码3 β-羟基类固醇脱氢酶-1的HSD 3B 1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作用。在这项研究中，我们研究了阿比特龙治疗的前列腺癌患者中雄激素和阿比特龙代谢相关基因多态性的意义。共纳入了2014年至2018年期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。从全血样本中获得基因组DNA，并通过基于PCR的技术对SRD 5A 2（rs 523349）、CYP 17 A1（rs743572）、CYP 17 A1（rs 2486758）和AKR 1C 3（rs 12529）进行基因分型。在99名患者中，32名（32.3%）、49名（49.5%）和18名（18.2%）患者分别携带SRD 5A 2的GG、GC和CC等位基因。多变量分析显示，与GG/GC等位基因相比，CC等位基因与治疗失败风险较低相关（风险比，0.43; 95%可信区间，0.20-0.87; P = 0.017）。在使用HSD 3B 1和SRD 5A 2多态性的组合模型中，与HSD 3B 1中AA和SRD 5A 2中GG/GC的组合相比，其他组合与多变量分析中治疗失败风险较低相关（风险比，0.34; 95%置信区间，0.17-0.62; P = 0.0003）。这项研究表明，SRD 5A 2遗传变异与阿比特龙治疗失败的风险相关。联合使用HSD 3B 1和SRD 5A 2基因变异可增强预后分层的能力。
Missense polymorphism in HSD3B1, encoding 3 beta-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.