Genetic Variation in IL-8 Associated with Increased Risk and Poor Prognosis of Breast Carcinoma Kaouther Snoussi, Wijden Mahfoudh, Noureddine Bouaouina, Slim Ben Ahmed, A. Noureddine Helal, and Lotfi Chouchane ABSTRACT: Interleukin-8 (IL-8), a potent chemoattrac- tant, has been demonstrated to contribute to human can- cer progression through its potential functions as a mito- genic, angiogenic, and motogenic factor. We designed a broad study to investigate whether genetic variation in IL-8 has implications for susceptibility to and prognosis in breast carcinoma. We used the allele-specific polymer- ase chain reaction to characterize the variation of the IL-8 promoter region for 308 unrelated Tunisian patients with breast carcinoma and 236 healthy control subjects. Asso- ciations of the clinicopathologic parameters and the ge- netic marker with the rates of the breast carcinoma- specific overall survival and the disease-free survival were assessed using univariate and multivariate analyses. A significantly increased risk of breast carcinoma was associated with heterozygous IL-8 (-251) TA (OR = 1.58, p = 0.02) and homozygous IL-8 (-251) AA (OR = 1.76, p = 0.01) variants. A significant association between the IL-8 (-251) AA homozygous genotype and the aggressive phenotype of breast carcinoma as defined by the high histological grade, auxiliary’s lymph node metastasis, and large tumor size was found. The IL-8 (-251) A allele manifested a significant as- sociation with decreased overall survival and disease-free survival for breast carcinoma patients. The polymor- phism in the promoter region of the IL-8 gene may not only represent a marker for the increased risk of breast carcinoma but also predict the clinical outcome. Human Immunology 67, 13–21 (2006). © American So- ciety for Histocompatibility and Immunogenetics, 2006. Published by Elsevier Inc. KEYWORDS: Breast carcinoma; polymorphism; prog- nosis; susceptibility; interleukin-8 ABBREVIATIONS AS-PCR allele-specific polymerase chain reaction DFS disease-free survival OVS overall survival INTRODUCTION Breast cancer is the most prevalent common malignancy among women around the world. It occurs in both hereditary and sporadic forms. Genetic factors are in- creasingly recognized as major contributors to breast cancer risk [1, 2]. Although genes with highly penetrat- ing mutations— exemplified by BRCA1 and BRCA2— confer high relative risks, they are rare in the general population and therefore the population-attributable risk is low. It is now suspected that most of the population- attributable genetic risk is due to a combination of common “low-penetrance” gene polymorphisms. The contribution of inflammation and inflammatory cells to the process of tumor development and progres- sion is increasingly recognized [3]. It is now evident that a substantial proportion of cancer cases worldwide arises from infection and chronic inflammation [4]. Both in- flammatory and tumor cells produce an assorted array of cytokines and chemokines, which mediate all aspects of From the Laboratoire d’Immuno-Oncologie Moléculaire, Faculté de Médecine de Monastir (K.S., W.M., N.B., L.C.) and Unité Génome, Diagnostic Immunitaire et Valorisation, Institut Supérieur de Biotechnologie de Monastir (A.N.H.), Université de Monastir, 5019 Monastir, Tunisia; and Department’s of Cancérologie Radiothérapie (N.B.) and Carcinologie Médicale (S.B.A.), CHU Farhat Hached, Sousse, Tunisia. Address reprint requests to: Professor Lotfi Chouchane, Laboratoire d’Immuno-Oncologie Moléculaire, Faculté de Médecine de Monastir, 5019 Monastir, Tunisie; Tel: 216-3-462 200; Fax: 216-3-460 737; E mail: lotfi.chouchane@planet.tn. Supported by le Ministère de la Recherche Scientifique et de Technologie et du Développement des Compétences, by le Ministère de l’Enseignement Supérieur, by le Ministère de la Santé Publique de la République Tunisienne. Human Immunology 67, 13–21 (2006) © American Society for Histocompatibility and Immunogenetics, 2006 0198-8859/06/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2006.03.018