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Inflammation, Genetic Polymorphisms in Proinflammatory Genes TNF-A, RANTES, and CCR5, and Risk of Pancreatic Adenocarcinoma

¹ Department of Community and Family Medicine, ² Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire; ³ Departments of Pediatrics, Microbiology and Immunology, Epidemiology and Population Health, and Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York; ⁴ Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts; and ⁵ Cancer Epidemiology Studies, Department of Epidemiology and Biostatistics, University of California, San Francisco, California

Requests for reprints: Eric J. Duell, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center 7927 Rubin Building, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-650-6202. E-mail: Eric.Duell{at}Dartmouth.Edu

Adenocarcinoma of the exocrine pancreas is the fourth leading cause of cancer-related death in men and women in the U.S. Cytokines and other proinflammatory mediators have been implicated in inflammatory pancreatic diseases including pancreatitis and cancer. We analyzed cytokine gene polymorphisms as risk factors for pancreatic cancer using questionnaire data obtained by in-person interviews and germ line DNA collected in a population-based case-control study of pancreatic cancer (532 cases and 1,701 controls) conducted in the San Francisco Bay Area. We used mass spectrometry and gel-based methods to genotype 308 cases and 964 population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression analysis and included adjustment for age, sex, and smoking. We assessed potential interactions between these polymorphisms, proinflammatory conditions (e.g., pancreatitis, ulcer, and obesity), and smoking as risk factors for pancreatic cancer. There was no overall association between pancreatic cancer risk and tumor necrosis factor- (TNF-A –308G/A), regulated upon activation, normally T cell–expressed, and presumably secreted (RANTES –403G/A), and CC chemokine receptor 5 (CCR5-32) polymorphisms. There was a nearly 7-fold increased relative risk estimate for pancreatic cancer in individuals with a history of pancreatitis (adjusted OR, 6.9; 95% CI, 3.4-14.1). Among patients with pancreatic cancer, pancreatitis was significantly associated with TNF-A –308 GA + AA (OR, 3.1; 95% CI, 1.3-7.4) and with RANTES –403 GA + AA (OR, 2.3; 95% CI, 1.0-5.4). There was evidence for a possible interaction between current active smoking and CCR5-32del. Our results lend support for the hypothesis that proinflammatory gene polymorphisms, in combination with proinflammatory conditions, may influence the development of pancreatic cancer. (Cancer Epidemiol Biomakers Prev 2006;15(4):726–31)

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