CHFR 启动子甲基化与局部晚期结肠癌疾病复发的关联。

Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer.

机构信息

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

出版信息

Clin Cancer Res. 2011 Jul 1;17(13):4531-40. doi: 10.1158/1078-0432.CCR-10-0763. Epub 2011 May 6.

DOI:10.1158/1078-0432.CCR-10-0763

PMID:21551253

Abstract

PURPOSE

This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.

EXPERIMENTAL DESIGN

A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999-2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan-Meier method, and Cox proportional hazards model.

RESULTS

Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.

CONCLUSIONS

The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence.

摘要

目的

本研究旨在确定 DNA 甲基化生物标志物是否与结肠癌患者的复发和生存相关。

实验设计

对 82 例接受美国癌症联合委员会（AJCC）高危 II 期或 III 期结肠癌根治性手术切除（1999-2007 年）的患者进行回顾性分析。采用焦磷酸测序法定量评估 DNA 甲基化状态。我们预先选择了三个肿瘤抑制基因和一个感兴趣的基因座；CHFR、ID4、RECK 和 MINT1。使用启动子区域中多个 CpG 位点的平均甲基化水平进行分析；将 15%或更高定义为甲基化阳性。通过对数秩检验、Kaplan-Meier 方法和 Cox 比例风险模型分析无复发生存率（RFS）和总生存率（OS）与甲基化状态的关系。

结果

ID4、MINT1 和 RECK 的甲基化水平与 RFS 或 OS 无关。CHFR 在 63%的患者中呈甲基化阳性。当甲基化状态分为二分类（阴性或低：<30%，高：≥30%）时，CHFR 甲基化高（44%）的患者 RFS 更差（P=0.006），OS 降低（P=0.069）。按分期分层时，CHFR 甲基化高与 III 期患者的 RFS 降低（P=0.004）和 OS 降低（P=0.010）相关。CHFR 甲基化高与 N2 疾病（P=0.04）和近端肿瘤（P=0.002）相关。多变量分析表明，AJCC T4 疾病和 CHFR 甲基化高（P=0.001 和 P=0.015）是复发的独立预测因素。