Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Clinical Research Coordination, Instituto Nacional de Câncer (INCA)-Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
PLoS One. 2013 Sep 27;8(9):e70878. doi: 10.1371/journal.pone.0070878. eCollection 2013.
To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC).
PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated.
PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI) = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth.
Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.
阐明卵巢癌（OC）中异常启动子高甲基化（PH）的生物学和临床影响作用。
通过定量甲基化特异性 PCR（QMSP）在训练集中评估 PGP9.5、HIC1、AIM1、APC、PAK3、MGMT、KIF1A、CCNA1、ESR1、SSBP2、GSTP1、FKBP4 和 VGF 的 PH。我们选择了两个基因（VGF 和 PGP9.5），在具有可用临床数据的更大独立验证（IV）集中进行进一步的 QMSP 分析。还评估了 VGF 基因的生物学相关性。
在 IV 组样本中，PGP9.5 和 VGF 的 PH 频率分别为 85%（316/372）和 43%（158/366），而对照组则没有观察到 PH。在有可用随访的 372 例 OC 病例中，PGP9.5 和 VGF PH 与患者生存更好相关[总生存（OS）的风险比（HR）分别为 0.59（95%置信区间（CI）为 0.42-0.84，p=0.004）和 0.73（95%CI 为 0.55-0.97，p=0.028），疾病特异性生存（DSS）分别为 0.57（95%CI 0.39-0.82，p=0.003）和 0.72（95%CI 0.54-0.96，p=0.027）。在多变量分析中，VGF PH 仍然是 OS（HR 0.61，95%CI 0.43-0.86，p<0.005）和 DSS（HR 0.58，95%CI 0.41-0.83，p<0.003）的独立预后因素。此外，PGP9.5 PH 与低分级、早期肿瘤和无残留疾病显著相关。在 OC 细胞系中强制表达 VGF 抑制了细胞生长。
我们的结果表明，VGF 和 PGP9.5 PH 是卵巢癌的潜在生物标志物。未来的研究需要进行具有纵向随访的确认队列，以在临床应用之前确定 VGF 和 PGP9.5 PH 的临床影响。
