Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy
Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy
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DOI：
10.1016/j.urolonc.2020.06.033
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发表时间：
2020-11-01
影响因子：
2.7
通讯作者：
Eto, Masatoshi
中科院分区：
文献类型：
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作者：
Shiota, Masaki;Endo, Satoshi;Eto, Masatoshi
目的：雄激素代谢是雄激素剥夺治疗（ADT）抵抗的关键因素。本研究旨在揭示CYP17A1、AKR1C3、HSD17B等雄激素代谢相关基因的遗传多态性对ADT期间血清睾酮水平的影响，以及对转移性前列腺癌（CaP）患者行ADT的预后的影响。材料和方法：本研究纳入了104例日本转移性CaP患者，其中80例患者在ADT期间的血清睾酮数据可用。检测CYP17A1 （rs743572）、AKR1C3 （rs12529）、HSD17B1 （rs605059）、HSD17B3 （rs2066479）和HSD17B4 （rs7737181）与ADT期间血清睾酮水平和预后（无进展生存期和总生存期）的相关性。用重组蛋白检测AKR1C3 H5Q的酶活性。结果：纯合子野生型（GG等位基因，中位数[四分位数范围]，12.0 ng/ml [8.0-19.0 ng/ml]） AKR1C3 rs12529与变异型（GC/CC等位基因，中位数[四分位数范围]，9.0 ng/ml [6.4-10.8 ng/ml]）相比，ADT期间血清睾酮水平较高。在多因素分析中，变异型（GC/CC等位基因）AKR1C3 rs12529与纯合子野生型（GG等位基因）相比，进展风险显著降低（风险比[95%置信区间]，0.47 [0.24-0.96],P = 0.039）。同时，其他遗传变异与ADT期间的血清睾酮和预后无关。野生型AKR1C3的酶活性与H5Q突变体相当。综上所述，本研究表明，AKR1C3多态性与ADT期间血清睾酮水平相关，可能是日本男性转移性前列腺癌进展为去势抵抗性前列腺癌的预后因素。版权所有。
Objective: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP).Materials and methods: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein.Results: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0-19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4-10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24-0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant.Conclusions: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP. (C) 2020 Elsevier Inc. All rights reserved.