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Background: Recent reports continue to support a link between chronic inflammation and progression to pancreatic cancer (PC). These cite an increased expression of proinflammatory mediators in PC but not in normal adjacent tissue, suggesting a possible mechanism of carcinogenesis. HYPOTHESIS: The association between inflammation and PC is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. METHODS: We conducted a case-control, candidate gene association study of 1,398 (1,354 Caucasian) eligible patients with histologically proven primary pancreatic ductal adenocarcinoma and 1,196 (1,189 Caucasian) healthy controls evaluated at a single institution from October 1, 2000 to the present. Inflammation-related candidate genes were selected using both literature review and bioinformatic analysis, followed by selection of tagged single nucleotide polymorphisms (tag SNPs). We used Illumina GoldenGate technology to genotype 768 tag SNPs of 61 candidate genes. The association of each SNP, under a log-additive genetic model, with risk for PC was evaluated using logistic regression, adjusting for known risk factors for PC. Statistical significance was set at <0.0001.RESULTS: Our sample was mostly Caucasians (96.8%) and 51.3% of cases and 57.3% of controls were male. When comparing cases and controls, there were statistically significant differences in sex (p=0.002), race (p=0.0002), smoking status (p<0.0001), BMI (p<0.0001), and personal history of first-degree relative with PC (p =0.0053). Restricting genetic analysis to Caucasians and adjusting for age, sex, smoking status, BMI, familial pancreatic cancer status, and diabetes diagnosed greater than two years prior to diagnosis of PC, single SNP analysis revealed an association between four SNPs in the neuronal nitric oxide synthase one gene (NOS1) and pancreatic cancer: rs547954 (p =0.00025 , OR = 1.31, (95% CI 1.13, 1.52), rs532967 (p=0.00049, OR = 1.29, (95% CI 1.12, 1.49)), rs3782203 (p=0.00055, OR = 1.27, (95% CI 1.11, 1.46)), and rs9658350(p = 0.00072, OR = 1.27, (95% CI 1.11, 1.45). In our genotyped data, the linkage disequilibrium (LD) between these SNPs ranged from 0.72 to 0.98. These SNPs have a close physical relationship on the NOS1 gene, within 2 LD blocks (8 kb and the other 28.7 kb) in a 38 kb region of chromosome 12.CONCLUSION: Of the 61 genes evaluated, only NOS1 had a significant association with PC and may be associated with risk of PC. NOS1 is not a well studied gene in PC. These preliminary findings warrant further studies to assess the impact of NOS1 on PC risk.