Post Graduate Program of Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil.
Pediatric Hematology-Oncology Research Program, Research Center (CPQ), Instituto Nacional de Câncer (INCA), Rua Andre Cavalcanti 37, Centro, Rio de Janeiro, 20231-050 Brazil.
Clin Epigenetics. 2017 Dec 12;9:128. doi: 10.1186/s13148-017-0431-6. eCollection 2017.
Wilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy. Somatic alterations occur at relatively low frequencies whereas epigenetic changes at 11p15 are the most common aberration. We analyzed long interspersed element-1 (LINE-1) methylation levels in the blastemal component of WT and normal kidney samples to explore their prognostic significance.
WT samples presented a hypomethylated pattern at all five CpG sites compared to matched normal kidney samples; therefore, the averaged methylation levels of the five CpG sites were used for further analyses. WT presented a hypomethylation profile (median 65.0%, 47.4-73.2%) compared to normal kidney samples (median 71.8%, 51.5-77.5%; < 0.0001). No significant associations were found between LINE-1 methylation levels and clinical-pathological characteristics. We observed that LINE-1 methylation levels were lower in tumor samples from patients with relapse (median methylation 60.5%) compared to patients without relapse (median methylation 66.5%; = 0.0005), and a receiving operating characteristic curve analysis was applied to verify the ability of LINE-1 methylation levels to discriminate WT samples from these patients. Using a cut-off value of 62.71% for LINE-1 methylation levels, the area under the curve was 0.808, with a sensitivity of 76.5% and a specificity of 83.3%. Having identified differences in LINE-1 methylation between WT samples from patients with and without relapse in this cohort, we evaluated other prognostic factors using a logistic regression model. This analysis showed that in risk stratification, LINE-1 methylation level was an independent variable for relapse risk: the lower the methylation levels, the higher the risk of relapse. The logistic regression model indicated a relapse risk increase of 30% per decreased unit of methylation (odds ratio 1.30; 95% confidence interval 1.07-1.57).
Our results reinforce previous data showing a global hypomethylation profile in WT. LINE-1 methylation levels can be suggested as a marker of relapse after chemotherapy treatment in addition to risk classification, helping to guide new treatment approaches.
Wilms 瘤（WT）是一种可治愈的小儿肾恶性肿瘤，但需要新的分子生物标志物来改善针对复发风险的治疗。体细胞改变的频率相对较低，而 11p15 的表观遗传改变是最常见的异常。我们分析了 WT 的胚性成分和正常肾脏样本中的长散布元件-1（LINE-1）甲基化水平，以探讨其预后意义。
WT 样本的所有五个 CpG 位点均表现出低甲基化模式，与匹配的正常肾脏样本相比；因此，进一步分析使用了五个 CpG 位点的平均甲基化水平。WT 表现出低甲基化谱（中位数 65.0%，47.4-73.2%），而正常肾脏样本为 71.8%（中位数 51.5-77.5%；<0.0001）。LINE-1 甲基化水平与临床病理特征之间无显著相关性。我们观察到，复发患者的肿瘤样本中的 LINE-1 甲基化水平较低（中位数甲基化 60.5%），而无复发患者的肿瘤样本中的 LINE-1 甲基化水平较高（中位数甲基化 66.5%；=0.0005），并应用接受者操作特征曲线分析来验证 LINE-1 甲基化水平区分这些患者的 WT 样本的能力。使用 LINE-1 甲基化水平的 62.71%作为截断值，曲线下面积为 0.808，灵敏度为 76.5%，特异性为 83.3%。在该队列中，我们在有和无复发的 WT 样本之间发现了 LINE-1 甲基化的差异，然后使用逻辑回归模型评估了其他预后因素。该分析表明，在风险分层中，LINE-1 甲基化水平是复发风险的一个独立变量：甲基化水平越低，复发风险越高。逻辑回归模型表明，每降低一个单位的甲基化，复发风险增加 30%（优势比 1.30；95%置信区间 1.07-1.57）。
我们的结果强化了之前的研究数据，表明 WT 存在整体低甲基化谱。LINE-1 甲基化水平可作为化疗后复发的标志物，除了风险分类外，还可帮助指导新的治疗方法。
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