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MDM2 Polymorphism, Survival, and Histology in Early-Stage Non–Small-Cell Lung Cancer

Rebecca Suk Heist, Wei Zhou, Lucian R. Chirieac, Thea Cogan-Drew, Geoffrey Liu, Li Su, Donna Neuberg, Thomas J. Lynch, John C. Wain, David C. Christiani

From the Massachusetts General Hospital; Harvard School of Public Health; and the Brigham and Women's Hospital, Boston, MA

Address reprint requests to David C. Christiani, MD, MPH, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115; e-mail: dchris{at}hsph.harvard.edu

Purpose MDM2 is a negative regulator of p53. The MDM2 309T/G polymorphism has been associated with differential MDM2 expression levels and inhibition of the p53 pathway. We hypothesized that the MDM2 G/G genotype may be associated with worse survival outcomes in lung cancer, especially in squamous cell cancers where p53 abnormalities are more common.

Patients and Methods We evaluated the relationship between MDM2 polymorphism status and overall survival (OS) among patients with early-stage non–small-cell lung cancer (NSCLC) treated with surgical resection at Massachusetts General Hospital from 1992 to 2000. Kaplan-Meier methods and the log-rank test were used to compare survival by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables.

Results There were 383 patients in the analysis. In the early-stage population as a whole, the G/G genotype seemed to be associated with worse OS on adjusted analysis (adjusted hazard ratio = 1.57; 95% CI, 1.03 to 2.40; P = .04). Among patients with squamous histology, OS was significantly worse among those with the G/G genotype (P = .0001 by log-rank test), with 5-year survival rates among the genotypes of 59% for T/T, 53% for T/G, and 7% for G/G.

Conclusion Our findings suggest that the G/G genotype of the MDM2 polymorphism is associated with worse OS among early-stage NSCLC patients, particularly those with squamous cell histology.

Supported by National Institutes of Health Grants No. CA074386, CA092824, and CA090578; Flight Attendants Medical Research Institute Young Clinical Scientist Award; American Cancer Society Postdoctoral Fellowship; and the Doris Duke Charitable Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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