Chang Yoon Soo, Wang Luo, Liu Diane, Mao Li, Hong Waun Ki, Khuri Fadlo R, Lee Ho-Young
Department of Thoracic/Head, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2002 Dec;8(12):3669-75.
The activities of insulin-like growth factors (IGFs) in regulating cell proliferation,differentiation, and apoptosis are modulated by a family of high-affinity specific IGF-binding proteins (IGFBPs), especially IGFBP-3, the most abundant IGFBP in circulation. Hypermethylation of the promoter represses the expression of the IGFBP-3 gene. The purpose of this study was to determine whether the methylation status of IGFBP-3 promoter influences the prognosis of non-small cell lung cancer (NSCLC).
Eighty-three patients with pathological stage I NSCLC who had undergone curative surgery were investigated for promoter hypermethylation of IGFBP-3 by methylation-specific PCR. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status of the IGFBP-3 promoter on various clinical parameters. IGFBP-3 was the only molecular parameter tested on these tissues in this study.
Hypermethylation of the IGFBP-3 promoter was found in 51 (61.5%) of the 83 tumors. The clinicopathological factors, such as age, histological type, histological grade, gender, and smoking status, of corresponding patients, did not exhibit statistically significant association with the methylation status of IGFBP-3 promoter. However, patients with a hypermethylated IGFBP-3 promoter had a significantly lower 5-year disease-specific, disease-free, and overall survival rate than did those without a methylated IGFBP-3 promoter (53.1% versus 86.1%, P = 0.006; 36.5% versus 76.2%, P = 0.007; and 38.9% versus 64.0%, P = 0.022, respectively). Moreover, multivariate analysis indicated that hypermethylation of the IGFBP-3 promoter was the only independent predictor for disease-free and disease-specific survival among the clinical and histological parameters tested.
Hypermethylation of the IGFBP-3 promoter, as measured by methylation-specific PCR, is a frequent phenomenon and strongly associated with poor prognosis among patients with stage I NSCLC.
胰岛素样生长因子（IGFs）在调节细胞增殖、分化和凋亡方面的活性受一类高亲和力特异性IGF结合蛋白（IGFBPs）调控，尤其是IGFBP - 3，它是循环中最丰富的IGFBP。启动子的高甲基化会抑制IGFBP - 3基因的表达。本研究旨在确定IGFBP - 3启动子的甲基化状态是否会影响非小细胞肺癌（NSCLC）的预后。
对83例接受根治性手术的病理I期NSCLC患者，采用甲基化特异性PCR检测IGFBP - 3启动子的高甲基化情况。进行双侧统计分析，以确定IGFBP - 3启动子甲基化状态对各种临床参数的预后影响。本研究中，IGFBP - 3是在这些组织上检测的唯一分子参数。
83个肿瘤中有51个（61.5%）检测到IGFBP - 3启动子高甲基化。相应患者的临床病理因素，如年龄、组织学类型、组织学分级、性别和吸烟状态，与IGFBP - 3启动子的甲基化状态无统计学显著关联。然而，IGFBP - 3启动子高甲基化的患者5年疾病特异性生存率、无病生存率和总生存率显著低于未发生甲基化的患者（分别为53.1%对86.1%，P = 0.006；36.5%对76.2%，P = 0.007；38.9%对64.0%，P = 0.022）。此外，多因素分析表明，在检测的临床和组织学参数中，IGFBP - 3启动子高甲基化是无病生存率和疾病特异性生存率的唯一独立预测因素。
通过甲基化特异性PCR检测发现，IGFBP - 3启动子高甲基化在I期NSCLC患者中是常见现象，且与预后不良密切相关。
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