Correlation between insulin-like growth factor-binding protein-3 promoter methylation and prognosis of patients with stage I non-small cell lung cancer.
OBJECTIVE
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).


METHODS
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.
Chang
Yoon Soo
YS
Department of Thoracic/Head, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wang
Luo
L
Liu
Diane
D
Mao
Li
L
Hong
Waun Ki
WK
Khuri
Fadlo R
FR
Lee
Ho-Young
HY
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism*; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012907:Smoking; D015996:Survival Rate
D017931:DNA Primers; D004273:DNA, Neoplasm; D018972:Insulin-Like Growth Factor Binding Protein 3