Diabetes mellitus and obesity has been implicated as a risk factor for pancreatic cancer. The insulin/insulin-like growth factor (IGF) axis may contribute to the observed correlations between diabetes, obesity and pancreatic cancer. To explore the genetic factors contributing to the development of pancreatic cancer, we evaluated six single nucleotide polymorphisms (SNPs) of the IGFI and IGFII gene in an ongoing hospital-based case-control study of pancreatic cancer conducted at M.D. Anderson Cancer Center during 2000 to present. A total of 997 patients with pathologically conformed pancreatic ductal adenocarcinoma and 783 healthy controls were enrolled in the study. Controls were recruited from spouses, non-blood relatives and friends of cancer patients seen at MDACC and were frequency-matched to cases by age (± 5 years), race and sex. Information on demographics, medical history, tobacco use, alcohol use, occupational history and family history of cancer was collected by personal interview using a structured questionnaire. Genotypes were determined using the Taqman technique. The main effects of the genotype and their interactions with other risk factors were investigated in 882 cases and 721 controls of Caucasians. Odds ratios (ORs) and 95% confidential intervals (CIs) were estimated using unconditional multivariate logistic regression models.
 Among the 6 SNPs examined, the IGFII 3’UTR C-233T (rs# 2230949) homozygous TT mutant had a significant protective effect on the risk of pancreatic cancer (P = 0.008). The OR (95% CI) was 0.059 (0.007-0.481) after adjusting for age, sex, diabetes, smoking, alcohol and family history of cancer. No significant main effects of the remaining 5 SNPs on the risk of pancreatic cancer were observed. However, there was a significant interaction betweenthe IGF1 3’-UTR G-177C (rs# 5742717) CC/CG genotype and diabetes on the risk ofpancreatic cancer. Compared with non-diabetic GG carriers, the adjusted OR (95% CI) was 1.01 (0.76-1.33) for non-diabetic CC/CG carriers, 2.22 (1.61-3.06) for diabetic GG carriers, and 5.12 (2.37-11.1) for diabetic CC/CG carriers (Pinteraction = 0.041). These risk estimates remained statistically significant in subgroup analysis among patients who had diabetes > 2 years before their pancreatic cancer diagnoses. No significant interaction of body mass index and genotype was observed. Our observations support the hypothesis that genetic variations in IGF pathway play an important role in modifying the risk of pancreatic cancer, especially those associated with diabetes. (Supported by NIH grant RO1 CA98380).

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA