Epigenomics AG, Berlin, Germany.
BMC Cancer. 2010 Jun 1;10:247. doi: 10.1186/1471-2407-10-247.
Various biomarkers for prediction of distant metastasis in lymph-node negative breast cancer have been described; however, predictive biomarkers for patients with lymph-node positive (LNP) disease in the context of distinct systemic therapies are still very much needed. DNA methylation is aberrant in breast cancer and is likely to play a major role in disease progression. In this study, the DNA methylation status of 202 candidate loci was screened to identify those loci that may predict outcome in LNP/estrogen receptor-positive (ER+) breast cancer patients with adjuvant anthracycline-based chemotherapy.
Quantitative bisulfite sequencing was used to analyze DNA methylation biomarker candidates in a retrospective cohort of 162 LNP/ER+ breast cancer patients, who received adjuvant anthracycline-based chemotherapy. First, twelve breast cancer specimens were analyzed for all 202 candidate loci to exclude genes that showed no differential methylation. To identify genes that predict distant metastasis, the remaining loci were analyzed in 84 selected cases, including the 12 initial ones. Significant loci were analyzed in the remaining 78 independent cases. Metastasis-free survival analysis was conducted by using Cox regression, time-dependent ROC analysis, and the Kaplan-Meier method. Pairwise multivariate regression analysis was performed by linear Cox Proportional Hazard models, testing the association between methylation scores and clinical parameters with respect to metastasis-free survival.
Of the 202 loci analysed, 37 showed some indication of differential DNA methylation among the initial 12 patient samples tested. Of those, 6 loci were associated with outcome in the initial cohort (n = 84, log rank test, p < 0.05).Promoter DNA methylation of cysteine dioxygenase 1 (CDO1) was confirmed in univariate and in pairwise multivariate analysis adjusting for age at surgery, pathological T stage, progesterone receptor status, grade, and endocrine therapy as a strong and independent biomarker for outcome prediction in the independent validation set (log rank test p-value = 0.0010).
CDO1 methylation was shown to be a strong predictor for distant metastasis in retrospective cohorts of LNP/ER+ breast cancer patients, who had received adjuvant anthracycline-based chemotherapy.
已经描述了各种用于预测淋巴结阴性乳腺癌远处转移的生物标志物；然而，对于接受特定全身治疗的淋巴结阳性（LNP）疾病患者，仍然非常需要预测生物标志物。DNA 甲基化在乳腺癌中异常，并且可能在疾病进展中起主要作用。在这项研究中，筛选了 202 个候选基因座的 DNA 甲基化状态，以鉴定那些可能预测接受辅助蒽环类药物为基础的化疗的 LNP/雌激素受体阳性（ER+）乳腺癌患者结局的基因座。
使用定量亚硫酸氢盐测序分析了 162 例接受辅助蒽环类药物为基础的化疗的 LNP/ER+乳腺癌患者的回顾性队列中 202 个候选生物标志物的 DNA 甲基化。首先，分析了 12 例乳腺癌标本中的所有 202 个候选基因座，以排除没有差异甲基化的基因。为了鉴定预测远处转移的基因，在 84 例选定病例中分析了其余基因座，包括 12 个初始病例。在其余 78 个独立病例中分析了有意义的基因座。使用 Cox 回归、时间依赖的 ROC 分析和 Kaplan-Meier 方法进行无转移生存分析。通过线性 Cox 比例风险模型进行两两多变量回归分析，测试了甲基化评分与与无转移生存相关的临床参数之间的关联。
在分析的 202 个基因座中，有 37 个在最初的 12 例患者样本中显示出一些差异 DNA 甲基化的迹象。其中，在最初的队列（n=84，对数秩检验，p<0.05）中，有 6 个基因座与结局相关。半胱氨酸双加氧酶 1（CDO1）启动子 DNA 甲基化在单变量和调整手术时年龄、病理 T 分期、孕激素受体状态、分级和内分泌治疗的两两多变量分析中被证实是独立验证队列中结局预测的强独立生物标志物（对数秩检验 p 值=0.0010）。
在接受辅助蒽环类药物为基础的化疗的 LNP/ER+乳腺癌患者的回顾性队列中，CDO1 甲基化被证明是远处转移的强预测因子。
