Peters Inga, Dubrowinskaja Natalia, Abbas Mahmoud, Seidel Christoph, Kogosov Michael, Scherer Ralph, Gebauer Kai, Merseburger Axel S, Kuczyk Markus A, Grünwald Viktor, Serth Jürgen
Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
Department of Pathology, Hannover Medical School, Hannover, Germany.
PLoS One. 2014 Mar 14;9(3):e91440. doi: 10.1371/journal.pone.0091440. eCollection 2014.
VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65-1.0) and a sensitivity of 0.73 (95% CI 0.43-0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.
血管内皮生长因子（VEGF）靶向治疗可提高转移性肾细胞癌（mRCC）患者的无进展生存期（PFS）和总生存期（OS）。识别肾细胞癌的分子表型可改善风险分层并预测临床病程。我们研究了基因特异性DNA高甲基化是否能预测接受抗VEGF治疗患者的PFS和OS。对18例接受靶向治疗患者的原发性肿瘤组织进行回顾性研究，采用定量甲基化特异性PCR分析CST6、LAD1、hsa-miR-124-3和hsa-miR-9-1 CpG岛。使用对数秩统计分析一线和序贯抗血管生成治疗的PFS和OS。确定预测一线治疗失败的敏感性和特异性。CST6和LAD1的高甲基化与PFS缩短（对数秩p = 0.009和p = 0.004）和OS缩短（p = 0.011和p = 0.043）均相关。CST6和LAD1高甲基化组与低甲基化组观察到的中位PFS分别为2.0个月和11.4个月。LAD1甲基化预测一线治疗的特异性为1.0（95%CI 0.65 - 1.0），敏感性为0.73（95%CI 0.43 - 0.90）。CST6和LAD1甲基化是候选表观遗传生物标志物，与PFS和OS呈现前所未有的关联，且对治疗反应预测具有特异性。在未来研究中，应考虑将DNA甲基化标志物用于更大患者队列的前瞻性评估。
