Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHUQ) Research Centre and Faculty of Pharmacy, Laval University, Québec, Canada.
Eur Urol. 2011 Dec;60(6):1226-34. doi: 10.1016/j.eururo.2011.06.020. Epub 2011 Jun 29.
The relationship between inherited germ-line variations in the 5α-reductase pathways of androgen biosynthesis and the risk of biochemical recurrence (BCR) after radical prostatectomy (RP) remains an unexplored area.
To determine the link between germ-line variations in the steroid-5α-reductase, α-polypeptide 1 (SRD5A1) and steroid-5α-reductase, α-polypeptide 2 (SRD5A2) genes and BCR.
DESIGN, SETTINGS, AND PARTICIPANTS: We studied retrospectively two independent cohorts composed of 526 white (25% BCR) and 320 Asian men (36% BCR) with pathologically organ-confined prostate cancer who had a median follow-up of 88.8 and 30.8 mo after surgery, respectively.
Patients were genotyped for 19 haplotype-tagging single nucleotide polymorphisms (htSNPs) in SRD5A1 and SRD5A2 genes, and their prognostic significance on prostate-specific antigen recurrence was assessed using Kaplan-Meier analysis and the Cox regression model.
After adjusting for all clinicopathologic risk factors, four SNPs (rs2208532, rs12470143, rs523349, and rs4952197) were associated with BCR in both whites and Asians. The strongest effect was conferred by the SRD5A2 V89L nonsynonymous SNP (rs523349C) with a hazard ratio (HR) of 2.87 (95% confidence interval [CI], 2.07-4.00; p = 4 × 10⁻¹⁰; 48% BCR). In addition, in whites, the combination of two SNPs, rs518673T in SRD5A1 and rs12470143A in SRD5A2, was associated with a reduced BCR rate for carriers of three or four alleles (HR: 0.37; 95% CI, 0.19-0.71; p=0.003;16% BCR) compared with noncarriers (38% BCR), whereas the SRD5A2 rs12470143A was significant in Asians (HR: 0.46; 95% CI, 0.28-0.73; p=0.001). Limitations of our study include few events of androgen-deprivation resistance or cancer-specific death.
Our study is the first to show positive associations of several SRD5A1 and SRD5A2 variations as independent predictors of BCR after RP.
雄激素生物合成的 5α-还原酶途径中的遗传种系变异与根治性前列腺切除术（RP）后生化复发（BCR）的风险之间的关系仍然是一个未探索的领域。
确定甾体-5α-还原酶，α-多肽 1（SRD5A1）和甾体-5α-还原酶，α-多肽 2（SRD5A2）基因中的种系变异与 BCR 之间的联系。
设计、设置和参与者：我们回顾性地研究了两个独立的队列，由 526 名白人（25%BCR）和 320 名亚洲男性（36%BCR）组成，这些男性患有病理器官局限的前列腺癌，手术后中位随访时间分别为 88.8 和 30.8 个月。
对 SRD5A1 和 SRD5A2 基因中的 19 个单核苷酸多态性（htSNP）进行了单倍型标记物（htSNP）的基因分型，并使用 Kaplan-Meier 分析和 Cox 回归模型评估了其对前列腺特异性抗原复发的预后意义。
在调整了所有临床病理危险因素后，在白人和亚洲人中，有四个 SNP（rs2208532、rs12470143、rs523349 和 rs4952197）与 BCR 相关。SRD5A2 V89L 非同义 SNP（rs523349C）的影响最强，其危险比（HR）为 2.87（95%置信区间[CI]，2.07-4.00；p=4×10⁻¹⁰；48%BCR）。此外，在白人中，两个 SNP（SRD5A1 中的 rs518673T 和 SRD5A2 中的 rs12470143A）的组合与携带三个或四个等位基因的携带者的 BCR 率降低相关（HR：0.37；95%CI，0.19-0.71；p=0.003；16%BCR）与非携带者（38%BCR）相比，而 SRD5A2 rs12470143A 在亚洲人中具有显著性（HR：0.46；95%CI，0.28-0.73；p=0.001）。本研究的局限性包括雄激素剥夺抵抗或癌症特异性死亡的事件较少。
我们的研究首次显示，SRD5A1 和 SRD5A2 多种变异作为 RP 后 BCR 的独立预测因子存在正相关。
