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RANTES Expression Is a Predictor of Survival in Stage I Lung Adenocarcinoma¹

Section of General Thoracic Surgery, Department of Surgery [C. J. M., M. D. I., G. C., M. B. O., D. G. B.], Section of Pulmonary Medicine and Critical Care, Department of Medicine [D. A. A.], Biostatistics [C-C. H.], Pathology [T. J. G., D. G. T.], Pediatrics [D. E. M., S. H.], University of Michigan, Ann Arbor, Michigan 48109

Purpose: The presence of an active lymphocytic response (ALR) in non-small cell lung cancer (NSCLC) tumors has previously been associated with a more favorable prognosis. The purpose of this study was to identify differences in global gene expression profiles between stage I NSCLC tumors with ALR (ALR+) and those without ALR (ALR-).

Experimental Design: Sixty-three stage I lung adenocarcinomas were analyzed for gene expression using Affymetrix oligonucleotide microarrays. Tumors were stratified into ALR+ and ALR- groups and compared for statistically significant differences in gene expression. Identified candidate genes were validated using both ELISA and immunohistochemistry. Follow-up data for these patients were collected and used to assess patient prognosis.

Results: Of the 63 tumors studied, 27 were ALR+ and 36 were ALR-. A total of 303 genes showed significant differences in gene expression between the two populations (t test, P < 0.02). Three of the genes overexpressed by ALR+ tumors were the chemokines: small inducible cytokine A4 (MIP-1ß), RANTES, and interferon inducible protein 10 (IP-10). Immunohistochemistry analysis showed that the tumor cells expressed these cytokines. ELISA showed that MIP-1ß and RANTES were overexpressed at the protein level by ALR+ tumors. Univariate Cox proportional hazards analysis showed that RANTES was a predictor of survival in stage I lung adenocarcinomas (P = 0.002).

Conclusion: When tested in the Cox univariate proportional hazards model, RANTES expression by lung adenocarcinoma cells is a predictor of survival in stage I NSCLC patients and may be useful as a prognostic factor in lung cancer.

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