Inflammation, genetic polymorphisms in proinflammatory genes TNF-A, RANTES, and CCR5, and risk of pancreatic adenocarcinoma.
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-alpha (TNF-A -308G/A), regulated upon activation, normally T cell-expressed, and presumably secreted (RANTES -403G/A), and CC chemokine receptor 5 (CCR5-Delta32) 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.
Duell
Eric J
EJ
Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA. Eric.Duell@Dartmouth.Edu
Casella
Daniel P
DP
Burk
Robert D
RD
Kelsey
Karl T
KT
Holly
Elizabeth A
EA
D000230:Adenocarcinoma / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics*; D012306:Risk; D012495:San Francisco / Q000453:epidemiology; D012907:Smoking / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D018946:Chemokine CCL5; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha