用于预测局限性前列腺癌根治术后生化复发的 DNA 甲基化特征。

DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer.

机构信息

Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, Philippe Lamy, Michael Borre, Søren Høyer, Torben F. Ørntoft, and Karina D. Sørensen, Aarhus University Hospital, Aarhus, Denmark; Peter Wild, University Hospital Zurich, Zurich, Switzerland; Wolfgang A. Schulz and Christian Arsov, Heinrich Heine University, Düsseldorf, Germany; and Tapio Visakorpi, University of Tampere and Tampere University Hospital, Tampere, Finland.

出版信息

J Clin Oncol. 2013 Sep 10;31(26):3250-8. doi: 10.1200/JCO.2012.47.1847. Epub 2013 Aug 5.

DOI:10.1200/JCO.2012.47.1847

PMID:23918943

Abstract

PURPOSE

Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential.

METHODS

Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses.

RESULTS

Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P < .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio [HR], 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P < .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13).

CONCLUSION

We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.

摘要

目的

前列腺癌（PC）的诊断和预后工具并不理想，导致对惰性 PC 的过度治疗和对侵袭性 PC 治疗时机的延误。在这里，我们鉴定了六个具有潜在诊断和预后能力的新的候选 DNA 甲基化标志物。

方法

利用基于微阵列的筛选和 20 例非恶性和 29 例 PC 组织标本的亚硫酸氢盐测序，鉴定了新的候选 PC 中 DNA 过度甲基化标志物。在丹麦、瑞士、德国和芬兰收集的 35 例非恶性前列腺组织样本、293 例根治性前列腺切除术（RP）样本（队列 1，训练）和 114 例恶性 RP 样本（队列 2，验证）中评估了诊断和预后潜力。通过接受者操作特征分析评估 PC 的敏感性和特异性。通过对数秩检验和单变量及多变量 Cox 回归分析评估 DNA 甲基化水平与生化复发之间的相关性。

结果

AOX1、C1orf114、GAS6、HAPLN3、KLF8 和 MOB3B 的高甲基化具有高度的肿瘤特异性（曲线下面积，0.89 至 0.98）。此外，在队列 1 的多变量分析中，高 C1orf114 甲基化与生化复发显著相关（危险比[HR]，3.10；95%置信区间，1.89 至 5.09），并在队列 2 中成功验证（HR，3.27；95%置信区间，1.17 至 9.12）。此外，在队列 1 中训练了一个具有显著意义的（P <.05）三基因预后甲基化特征（AOX1/C1orf114/HAPLN3），将患者分为低甲基化和高甲基化亚组（HR，1.91；95%置信区间，1.26 至 2.90），并在队列 2 中得到验证（HR，2.33；95%置信区间，1.31 至 4.13）。