The role of gene-environment interaction in the development of pancreatic cancer

Abstract

The aetiology for sporadic pancreatic adenocarcinoma is poorly characterized. Familial/hereditary causes account for about 10% cases and tobacco smoking is a well- established risk, however it is only responsible for about a third of cases. DNA repair mechanisms restore the genome damage caused by carcinogens including those derived from tobacco smoking. Increasing attention is being focused on single nucleotide polymorphisms, which exist amongst various physiological pathways including DNA repair mechanisms, and account for inter-individual variation in risk for cancer. This study is an effort to investigate the impact of family history of malignancy, tobacco smoking and selected genetic polymorphisms involved in DNA repair on pancreatic ductal adenocarcinoma development. A hospital-based case-control study of pancreatic adenocarcinoma cases and hospital- based controls was undertaken at the Freeman Hospital between 2005-2006. Pancreatic cancer cases were ascertained based on histology, cytology or a combination of clinical findings, tumour marker levels and progressive radiological changes. All participants were interviewed to establish a detailed clinical, family history and tobacco smoking (MONICA questionnaire) A sample of peripheral blood was obtained for genotyping of specific Base Excision repair genotypes – hOGG1, XRCC194, XRCC280, XRCC399 and APE148. Statistical analysis was performed on SPSS v16. Odds ratios (95% CI) were calculated for individual variables. Tobacco smoking was confirmed to be a risk factor for pancreatic cancer [OR (95% CI) on univariate: ever smoker [(present and past smokers) OR 3.01 (95% CI 1.73 to 5.24)] and multivariate analysis: present smokers [OR = 8.531 (3.198 to 22.759) and past smokers OR = 5.862 (2.223 to 15.460)]. Importantly a significantly decreased cumulative tobacco exposure was seen amongst pancreatic cancer cases with a family history of cancer [mean (SD): 30.00 (24.77) pack-years] as compared those who did not have such a history [44.69 (28.47) pack-years p=0/023]. No specific overall increased risk was associated with the individual base excision repair genotypes on both uni- variate and multi-variate analysis. Tobacco smoking is a risk factor and appears to play a more important role (for pancreatic cancer development) in the presence of a family history of cancer. Small risks associated with SNP’s are difficult to tease out from small studies like the current one. Larger multi institutional studies (as have been achieved for e.g. Lung Cancer) are required to confirm this latter finding and perform pooled analysis of data for specific sequence variants within a target biochemical pathway to uncover the risks associated with these genes.