This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, C. Articles by Khuri, F. R. Search for Related Content PubMed PubMed Citation Articles by Lu, C. Articles by Khuri, F. R. Social Bookmarking                            What's this?

Prognostic Factors in Resected Stage I Non–Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers

From the Departments of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, Pathology, and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Institut Gustave Roussy, Villejuif, France; and Winship Cancer Institute, Emory University, Atlanta, GA

Address reprint requests to Charles Lu, MD, SM, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030-4009; e-mail: clu{at}mdanderson.org

PURPOSE: To analyze the prognostic significance of six molecular biomarkers (death-associated protein kinase [DAPK] promoter methylation, interleukin-10 [IL-10] protein expression, cyclooxygenase-2 [COX-2] mRNA expression, human telomerase reverse transcriptase catalytic subunit [hTERT] mRNA expression, retinoic acid receptor-beta [RAR-ß] mRNA expression, and K-ras mutational status) in stage I non–small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS: Biomarker analyses were performed on tumors from 94 patients with stage I NSCLC who underwent surgical resection at our institution. A minimum follow-up period of 5 years was required. DAPK methylation was assessed by methylation-specific polymerase chain reaction (PCR). RAR-ß, COX-2, and hTERT mRNA levels were determined by in situ hybridization with digoxigenin-labeled antisense riboprobes. K-ras mutation status was determined by the PCR–primer introduced restriction with enrichment for mutant alleles method. IL-10 protein expression was analyzed by immunohistochemistry using a polyclonal antihuman IL-10 antibody. Cancer-specific survival was analyzed with a Cox proportional hazards model. To identify independent prognostic factors, a stepwise selection method was used.

RESULTS: DAPK methylation, IL-10 lack of expression, COX-2 expression, hTERT expression, RAR-ß expression, and K-ras mutations were observed in 46.8%, 29.8%, 59.6%, 34.0%, 23.4%, and 34.0% of patients, respectively. In the final model, DAPK methylation and IL-10 lack of expression were significant negative prognostic factors for cancer-specific survival, whereas COX-2 expression was of borderline significance.

CONCLUSION: In this cohort of resected stage I NSCLC patients, molecular markers that independently predict cancer-specific survival have been identified. The prognostic roles of DAPK methylation, IL-10, and other biomarkers in NSCLC merit further investigation.

Supported in part by National Cancer Institute grant No. K12 CA088084 and the Department of Defense, Biology, Education, Screening, Chemoprevention, and Treatment of Lung Cancer grant No. DAMD17-01-1-0689 and Translational Approaches for the Reversal, Genetic, Evaluation and Treatment of Lung Cancer grant No. DAMD17-02-1-0706.

Presented in part at the 93rd Annual Meeting of the American Association for Cancer Research, San Francisco, CA, April 6–10, 2002.

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. T. McCabe, J. C. Brandes, and P. M. Vertino Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications Clin. Cancer Res., June 15, 2009; 15(12): 3927 - 3937. [Abstract] [Full Text] [PDF]

				R. METZGER, D. VALLBOHMER, C. MULLER-TIDOW, H. HIGASHI, E. BOLLSCHWEILER, U. WARNECKE-EBERZ, J. BRABENDER, S. E. BALDUS, H. XI, W. E. BERDEL, et al. Increased Human Telomerase Reverse Transcriptase (hTERT) mRNA Expression but not Telomerase Activity is Related to Survival in Curatively Resected Non-small Cell Lung Cancer Anticancer Res, April 1, 2009; 29(4): 1157 - 1162. [Abstract] [Full Text] [PDF]

				A. L. Van Dyke, M. L. Cote, G. M. Prysak, G. B. Claeys, A. S. Wenzlaff, V. C. Murphy, F. Lonardo, and A. G. Schwartz COX-2/EGFR expression and survival among women with adenocarcinoma of the lung Carcinogenesis, September 1, 2008; 29(9): 1781 - 1787. [Abstract] [Full Text] [PDF]

				M. V. Brock, C. M. Hooker, E. Ota-Machida, Y. Han, M. Guo, S. Ames, S. Glockner, S. Piantadosi, E. Gabrielson, G. Pridham, et al. DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer N. Engl. J. Med., March 13, 2008; 358(11): 1118 - 1128. [Abstract] [Full Text] [PDF]

				F. Barlesi, G. Giaccone, M. I. Gallegos-Ruiz, A. Loundou, S. W. Span, P. Lefesvre, F. A.E. Kruyt, and J. A. Rodriguez Global Histone Modifications Predict Prognosis of Resected Non Small-Cell Lung Cancer J. Clin. Oncol., October 1, 2007; 25(28): 4358 - 4364. [Abstract] [Full Text] [PDF]

				I. Bolonaki, A. Kotsakis, E. Papadimitraki, D. Aggouraki, G. Konsolakis, A. Vagia, C. Christophylakis, I. Nikoloudi, E. Magganas, A. Galanis, et al. Vaccination of Patients With Advanced Non-Small-Cell Lung Cancer With an Optimized Cryptic Human Telomerase Reverse Transcriptase Peptide J. Clin. Oncol., July 1, 2007; 25(19): 2727 - 2734. [Abstract] [Full Text] [PDF]

				L Taillade, F Penault-Llorca, T Boulet, P Fouret, S Michiels, E Taranchon, G Mountzios, P Validire, J Domont, P Girard, et al. Immunohistochemichal expression of biomarkers: a comparative study between diagnostic bronchial biopsies and surgical specimens of non-small-cell lung cancer Ann. Onc., June 1, 2007; 18(6): 1043 - 1050. [Abstract] [Full Text] [PDF]

				T. Tokuhara, N. Hattori, H. Ishida, T. Hirai, M. Higashiyama, K. Kodama, and M. Miyake Clinical Significance of Aminopeptidase N in Non-Small Cell Lung Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 3971 - 3978. [Abstract] [Full Text] [PDF]

				L. Wang, Q. Wei, L.-E Wang, K. D. Aldape, Y. Cao, M. F. Okcu, K. R. Hess, R. El-Zein, M. R. Gilbert, S. Y. Woo, et al. Survival Prediction in Patients With Glioblastoma Multiforme by Human Telomerase Genetic Variation J. Clin. Oncol., April 1, 2006; 24(10): 1627 - 1632. [Abstract] [Full Text] [PDF]

				J. Tsurutani, J. Fukuoka, H. Tsurutani, J. H. Shih, S. M. Hewitt, W. D. Travis, J. Jen, and P. A. Dennis Evaluation of Two Phosphorylation Sites Improves the Prognostic Significance of Akt Activation in Non-Small-Cell Lung Cancer Tumors J. Clin. Oncol., January 10, 2006; 24(2): 306 - 314. [Abstract] [Full Text] [PDF]

				C. R. Mulligan, A. D. Meram, C. D. Proctor, H. Wu, K. Zhu, and A. J. Marrogi Unlimited Access to Care: Effect on Racial Disparity and Prognostic Factors in Lung Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2006; 15(1): 25 - 31. [Abstract] [Full Text] [PDF]

				Y. T. Kim, S. J. Park, S. H. Lee, H. J. Kang, S. Hahn, C. H. Kang, S. W. Sung, and J. H. Kim Prognostic implication of aberrant promoter hypermethylation of CpG islands in adenocarcinoma of the lung J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1378 - 1378. [Abstract] [Full Text] [PDF]

				S. Mocellin, F. M. Marincola, and H. A. Young Interleukin-10 and the immune response against cancer: a counterpoint J. Leukoc. Biol., November 1, 2005; 78(5): 1043 - 1051. [Abstract] [Full Text] [PDF]

				F. R. Hirsch and S. M. Lippman Advances in the Biology of Lung Cancer Chemoprevention J. Clin. Oncol., May 10, 2005; 23(14): 3186 - 3197. [Abstract] [Full Text] [PDF]