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Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer¹

Departments of Thoracic/Head and Neck Medical Oncology [Y. S. C., L. W., L. M., F. R. K., W. K. H., H-Y. L.], and Biostatistics [D. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: 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).

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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