Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone
Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone
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DOI：
10.1001/jamanetworkopen.2019.0115
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发表时间：
2019-02-01
影响因子：
13.8
通讯作者：
Eto, Masatoshi
中科院分区：
文献类型：
--
作者：
Shiota, Masaki;Narita, Shintaro;Eto, Masatoshi
重要性最近，编码3β-羟基类固醇脱氢酶-1的HSD3B1基因多态性已被证明与前列腺癌去雄激素治疗(ADT)的肿瘤预后有关。阿比特龙联合ADT已证实对生存有利。目的探讨HSD3B1基因错义多态在接受原发ADT或阿比特龙治疗的男性患者中的意义。设计、背景和参与者这项预后研究包括1993年6月至2005年7月期间的日本转移性激素敏感型前列腺癌和2014年9月至2018年2月期间的去势耐受前列腺癌患者。从患者的全血样本中提取基因组DNA，用Sanger测序法进行HSD3B1(rs1047303,1245C)的基因分型。研究对象为转移性激素敏感型前列腺癌的原发ADT和去势耐受前列腺癌的阿比特龙。主要结果和测量HSD3B1的基因型与临床病理参数和肿瘤预后的关系，包括前列腺特异性抗原应答、无进展生存期、治疗无失败生存期和总生存期。结果203名男性中，104名在原发ADT队列(中位数[四分位数范围]，72[67-76]岁)，99名男性在阿比特龙组(中位数[四分位数范围]，年龄)。74[67-80]岁)。大多数患者在每个队列中都有转移性病变。在原发ADT的队列中，携带HSD3B1基因杂合子和纯合子变异类型的男性比携带纯合子野生型的男性有更高的进展风险(风险比[HR]，2.34；95%CI，1.08-4.49；P=.03)，但没有任何原因导致的死亡风险(HR，1.36；95%CI，0.52-2.92；P=.50)。相反，在阿比特龙队列中，携带HSD3B1基因变异类型的男性与携带纯合子野生型的男性相比，表现出较低的进展风险(HR，0.32；95%CI，0.12-0.69；P=.006)和较低的全因死亡风险(HR，0.40；95%CI，0.13-0.94；P=.04)。结论本研究表明，HSD3B1基因变异与日本男性原发性ADT和阿比特龙之间的肿瘤预后明显相关，这表明HSD3B1基因变异在不同种族的原发性ADT中具有普遍意义，并有望成为ADT和阿比特龙的生物预测指标。
IMPORTANCE Recently, genetic polymorphism in HSD3B1 encoding 3 beta-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear.OBJECTIVE To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone.DESIGN, SETTING, AND PARTICIPANTS This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing.EXPOSURES Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer.MAIN OUTCOMES AND MEASURES The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined.RESULTS Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P =.03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P =.50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P =.006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P =.04) compared with men carrying homozygous wild type.CONCLUSIONS AND RELEVANCE This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.