Genetic variability of the p16 locus and pancreatic cancer susceptibility

This thesis project deals with the genetic variability of p16 gene and its possible role in pancreatic cancer. There are two cell types, with different functions in the pancreas, the exocrine and the endocrine cells. More than 95% of pancreatic cancers (PC) are classified as exocrine tumors. The most common exocrine tumor is the pancreatic ductal adenocarcinoma (PDAC) which accounts for about 90% of all exocrine PC. PDAC is the most fatal form of PC with mortality rates almost identical to its incidence rates. The 5 year survival rate is less than 4%. Surgical resection has limited potential for cure, with less than 20% of patients eligible for surgery with curative intent, due to local spread or metastasis. PDAC is one of the most lethal cancers because it is usually diagnosed at an advanced stage and is resistant to therapy. Several studies suggest that pancreatic carcinogenesis involves a complex interaction between SNPs and non-genetic risk factors. Cigarette smoking and type II diabetes are clear risk factors for pancreatic cancer, while the association of pancreatic cancer with diet, BMI and alcohol consumption is less clear. P16 is a tumor suppressor protein, that in humans is encoded by the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene. The CDKN2A gene is frequently mutated or deleted in a wide variety of tumors and is a pleiotropic gene involved in the susceptibility to different cancers (basal cell carcinoma, breast cancer, melanoma, glioma) and other diseases (Type 2 diabetes, coronary artery calcification, coronary heart disease, aortic and Intracranial aneurysm, myocardial infarction). The aim of this study was to verify if the genetic variability of CDKN2A is associated with the risk of developing PDAC. The study population included 2.857 cases of PDAC and 6.111 healthy controls, from Germany, Czech Republic, Greece, Italy, Lithuania, Poland, Netherlands, UK and Japan. For each subject detailed information on gender, age and stage was obtained. The samples were collected by the PANcreatic Disease ReseArch (PANDoRA), consortium: we selected tagging SNPs in CDKN2A and we genotyped them in cases and controls. The order of DNA of cases and controls was randomized on PCR plates in order to analyze an equal number of cases and controls at the same time. All genotyping was carried out using KASPar or TaqMan assays. Statistical analysis was performed by the STATA software. Unconditional logistic regression, calculating odds ratios (OR) and 95% confidence intervals (95% CI) was performed, using PDAC cases and healthy controls to test the possible association of the selected SNPs. All analyses were adjusted for age at diagnosis/age at recruitment, gender and country of origin. Promising results were found for 1 SNP of CDKN2B gene