A functional polymorphism in the promoter region of leptin gene increases susceptibility for non-small cell lung cancer Ricardo Ribeiro a,d , Ana Paula Arau ´ jo a , Ana Coelho a , Raquel Catarino a , Daniela Pinto a , Anto ´nio Arau ´ jo b , Carmen Calc ¸ada c , Carlos Lopes a,d , Rui Medeiros a,d, * a Molecular Oncology – CI, Portuguese Institute of Oncology, Porto, Portugal b Medical Oncology Department, Portuguese Institute of Oncology, Porto, Portugal c Radiotherapy Department, Portuguese Institute of Oncology, Porto, Portugal d ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Portugal ARTICLE INFO Article history: Received 5 December 2005 Received in revised form 30 January 2006 Accepted 2 February 2006 Available online 19 April 2006 Keywords: Leptin Lung cancer Genetic polymorphism Risk Cigarette smoke ABSTRACT Leptin hormone and receptor have been associated to cancer development and were iden- tified in lung tissue. In this study, a functional polymorphism in the 5 0 flanking region of the leptin gene (LEP À2548 G/A) was found to increase susceptibility for non-small cell lung cancer [odds ratio (OR), 1.97; 95% confidence interval (CI), 1.13–3.43]. Age-adjusted logistic regression analysis in men indicated an association of AA genotype with adenocarcinoma (OR, 4.29; CI, 1.64–11.72) and squamous cell carcinoma (OR, 3.19; CI, 1.26–8.13). Logistic regression analysis confirmed the AA genotype as an independent risk factor for lung cancer after adjustment for age and gender (OR, 2.57; CI, 1.34–4.92). The AA genotype was overrepresented only in patients with non-metastatic disease (OR, 1.86; CI, 1.13– 3.04). Kaplan–Meier analysis demonstrated an earlier age of onset for lung cancer in AA car- riers (P = 0.023). Results suggest the existence of genetic susceptibility for lung cancer in carriers of this LEP functional polymorphism. Further studies are warranted to extend knowledge of leptin involvement in lung cancer. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Lung cancer is a widespread disease, with high incidence rates and leading mortality worldwide. In Europe the number of incident cases and cancer deaths from lung cancer in 2002 was 199,844 and 191,301, respectively. 1 Carcinogenesis in the lung is a multi-step process of pro- gressive disorganization characterized by events over latent periods of time, resulting from exposure to environmental in- sults. 2 Cigarette smoking is a major risk factor for 85% of lung cancers, although only 1 in 10 life-smokers will develop lung cancer, 3 suggesting individual differences in susceptibility that may be explained by the genetic profile. Accordingly, genetic polymorphisms have been analysed to ascertain their role in lung cancer susceptibility, prognostic and predictive value. 4,5 Leptin has relevant roles in cell growth, differentiation and angiogenesis 6–8 supporting its involvement in cancer develop- ment and progression. The long isoform leptin receptor (LEPRb) was identified in normal human lung tissue and in lung squamous cell cancer derived cell line (SQ-5), 7 suggest- ing that the lung is a peripheral site of action for leptin. Cumulatively, Tsuchiya and co-workers 7 observed a stimula- tory action for human recombinant leptin on SQ-5 cell prolif- eration mediated through MAP kinase signalling. 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.02.004 * Corresponding author: Present address: Molecular Oncology – CI, Instituto Portugue ˆs de Oncologia, Porto; Edifı´cio Laborato ´ rios – PISO 4; R. Dr. Ant. Bernardino Almeida, 4200-072 Porto, Portugal. Tel.: +351 22 508 4000; fax: +351 22 508 4001. E-mail address: ruimedei@ipoporto.min-saude.pt (R. Medeiros). EUROPEAN JOURNAL OF CANCER 42 (2006) 1188 – 1193 available at www.sciencedirect.com journal homepage: www.ejconline.com