Department of Urology Cancer Center, Kaohsiung Medical University Hospital, Taiwan.
J Intern Med. 2012 May;271(5):499-509. doi: 10.1111/j.1365-2796.2011.02449.x. Epub 2011 Sep 29.
Accumulating evidence indicates that oestrogens have significant direct effects on normal prostate development and carcinogenesis. The majority of the biological activities of oestrogens are mediated through the oestrogen receptor (ER), which functions as a hormone-inducible transcription factor to regulate target gene expression by binding to oestrogen response elements (EREs) in the regulatory regions of target genes. Sequence variants in EREs might affect the ER-ERE interaction and subsequent physiological activities. Therefore, we tested whether common single-nucleotide polymorphisms (SNPs) inside EREs are related to the clinical outcomes of androgen-deprivation therapy (ADT) in men with prostate cancer.
We systematically evaluated 49 ERE SNPs predicted using a genome-wide database in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed using Kaplan-Meier analysis and a Cox regression model.
Based on multiple hypothesis testing, BNC2 rs16934641 was found to be associated with disease progression; in addition, TACC2 rs3763763 was associated with PCSM, and ALPK1 rs2051778 and TACC2 rs3763763 were associated with ACM. These SNPs remained significant in multivariate analyses that included known clinicopathological predictors. Moreover, a combined genotype effect on ACM was observed when ALPK1 rs2051778 and TACC2 rs3763763 were analysed in combination. Patients with a greater number of unfavourable genotypes had a shorter time to ACM during ADT (P for trend <0.001).
The incorporation of ERE SNPs into models with known predictors might improve outcome prediction in patients with prostate cancer receiving ADT.
越来越多的证据表明，雌激素对正常前列腺的发育和癌变有显著的直接作用。雌激素的大多数生物学活性是通过雌激素受体（ER）介导的，ER 作为一种激素诱导的转录因子，通过与靶基因调控区的雌激素反应元件（ERE）结合，调节靶基因的表达。ERE 中的序列变异可能影响 ER-ERE 相互作用和随后的生理活性。因此，我们检测了 ERE 内常见的单核苷酸多态性（SNP）是否与接受雄激素剥夺治疗（ADT）的前列腺癌患者的临床结局有关。
我们系统地评估了在接受 ADT 治疗的 601 名晚期前列腺癌男性中，使用全基因组数据库预测的 49 个 ERE SNP。使用 Kaplan-Meier 分析和 Cox 回归模型评估这些 SNP 对 ADT 后疾病进展、前列腺癌特异性死亡率（PCSM）和全因死亡率（ACM）的预后意义。
经过多重假设检验，发现 BNC2 rs16934641 与疾病进展相关；此外，TACC2 rs3763763 与 PCSM 相关，ALPK1 rs2051778 和 TACC2 rs3763763 与 ACM 相关。在包括已知临床病理预测因素的多变量分析中，这些 SNP 仍然具有统计学意义。此外，当联合分析 ALPK1 rs2051778 和 TACC2 rs3763763 时，观察到 ACM 的联合基因型效应。在 ADT 期间，具有更多不利基因型的患者 ACM 时间更短（趋势 P<0.001）。
将 ERE SNP 纳入具有已知预测因子的模型中，可能会提高接受 ADT 的前列腺癌患者的预后预测能力。
