Identification of new germline variants associated with the risk of developing pancreatic cancer using genome-wide data

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease with a poor prognosis. The high mortality of PDAC is due to the absence of specific symptoms, diagnostic markers useful for early detection, and the absence of curative therapy. The current knowledge on PDAC susceptibility includes environmental and genetic risk factors. Tools to identify individuals at high risk of developing PDAC would be useful to improve the chances of early detection. The rising availability of genome-wide association studies (GWAS) data has prompted the development of new epidemiological approaches that use the genotypes of the GWAS to perform new focused analyses, based not only on the level of statistical significance, but on the a priori knowledge on the investigated variants. Our aims were the identification of new PDAC risk loci, and the identification of non-genetic risk factors through secondary analysis approaches. The long-term aim was the development of a tool to stratify the risk of developing PDAC in the general population. To identify new PDAC risk loci, we focused our analyses on a group of polymorphic functional regions, in particular the polymorphisms of the long non-coding RNAs (lncRNA), micro-RNAs (miRNA), miRNA targets and the pancreatic expression quantitative trait loci (eQTL) in a two phase study that included more than 20,000 individuals. We generated a polygenic risk score (PRS) using thirty known PDAC risk single nucleotide polymorphisms (SNPs) and a multifactorial risk score (MRS) with the addition of environmental risk variables. To study the causal effect of the suggested PDAC non-genetic risk factors, we performed a two-sample Mendelian Randomisation (MR) study, using the genetic variants associated with PDAC risk factors in place of the directed measurement of the risk factor exposures. We identified one SNP (rs7046076) that reached the genome-wide significance threshold (p<5×10-8) with an OR of 1.13, (95% CI 1.09-1.18, p=9.73x10-9). The PRS and MRS were associated with increased PDAC risk and reached high statistical significance: OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 for the PRS, and OR+14.37, 95% CI 5.57 to 37.09, p=3.64×10−8 for the MRS. With the MR approach we found evidence for a causal effect of body mass index (BMI) on PDAC risk (OR=1.43, 95% CI 1.20 to 1.71, p=8.43×10−5). In conclusion, using a secondary-analyses approach we identified a novel PDAC susceptibility variant. In addition, we tested for the first time a PRS and an MRS for PDAC Finally, we demonstrated the causal association of the increased BMI with increased PDAC risk. All these results could represent first steps for the development of tools for PDAC risk stratification.