Pharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval CHUQ Research Center, and Faculty of Pharmacy, and L'Hôtel-Dieu de Quebec, CHUQ Research Center and Faculty of Medicine, Laval University, Québec, Canada.
J Clin Endocrinol Metab. 2011 Sep;96(9):E1550-7. doi: 10.1210/jc.2011-1049. Epub 2011 Jul 6.
The prognostic relevance of inherited variations in hormone-related genes in the context of prostate cancer (PCa) progression has not been well studied. Of these, UDP-glucuronosyltransferase (UGT) gene products lead to inactivation of steroids.
Our objective was to determine whether polymorphisms in five UGT genes, involved in steroid metabolism, are associated with the risk of biochemical recurrence after radical prostatectomy (RP) and to examine their relationship with hormonal exposure.
The study included 526 Caucasian and 320 Asian men who underwent RP for clinically localized PCa. The relationship between genotypes and biochemical recurrence were assessed with multivariate Cox proportional hazard models. Plasma steroids were measured using specific and sensitive mass spectrometry-based methods.
The presence of at least two deleted copies of UGT2B17 and UGT2B28 genes resulted in a hazard ratio of 2.26 (95% confidence interval = 1.41-3.61; P = 0.0007) for Caucasians and 2.16 (95% confidence interval = 1.24-3.73; P = 0.006) for Asians. A positive association was observed only between UGT2B17 deletion and the Gleason score in Asians, whereas no other interaction was shown with prostate-specific antigen, Gleason score, and TNM (tumor node metastasis) staging. Patients carrying UGT2B17 deletions and those with three deleted UGT2B copies had significantly lower androgen glucuronides, in support of an altered androgen metabolism.
This study is the first to recognize the prognostic significance of common deletions in steroid inactivation pathways in localized PCa after RP. Alteration of circulating steroid levels associated with UGT2B gene deletions further support the notion that such inherited genomic deletions have the potential to modify hormonal exposure and risk of recurrence.
激素相关基因的遗传变异在前列腺癌（PCa）进展中的预后相关性尚未得到充分研究。在这些基因中，UDP-葡萄糖醛酸基转移酶（UGT）基因产物导致类固醇失活。
我们的目的是确定参与类固醇代谢的五个 UGT 基因中的多态性是否与根治性前列腺切除术后（RP）生化复发的风险相关，并研究它们与激素暴露的关系。
该研究纳入了 526 名白种人和 320 名亚洲人，他们因临床局限性 PCa 接受了 RP。使用多变量 Cox 比例风险模型评估基因型与生化复发之间的关系。使用特异性和敏感的基于质谱的方法测量血浆类固醇。
至少存在两个 UGT2B17 和 UGT2B28 基因缺失拷贝的存在导致白种人危险比为 2.26（95%置信区间=1.41-3.61；P=0.0007），亚洲人为 2.16（95%置信区间=1.24-3.73；P=0.006）。仅在亚洲人中观察到 UGT2B17 缺失与 Gleason 评分之间存在正相关，而与前列腺特异性抗原、Gleason 评分和 TNM（肿瘤节点转移）分期无其他相互作用。携带 UGT2B17 缺失的患者和携带三个缺失 UGT2B 拷贝的患者雄激素葡萄糖醛酸苷显著降低，支持雄激素代谢改变的观点。
本研究首次认识到 RP 后局部 PCa 中类固醇失活途径常见缺失的预后意义。与 UGT2B 基因缺失相关的循环类固醇水平的改变进一步支持这样一种观点，即这种遗传基因组缺失有可能改变激素暴露和复发风险。
