Background Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.
Objective We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.
Methods We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.
Results The scores 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 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).
Conclusion We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
- pancreas and biliary tract
- genetic epidemiology
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AAG and MG are joint first authors.
FC and DC are joint last authors.
AAG and MG contributed equally.
Contributors DC and FC conceived the study. MG, CR and AAG performed experimental work. DC, MG and AAG performed data analysis. All other authors contributed to the collection of samples and data. MG, AAG, CR, DC and FC drafted the manuscript, and all other authors took part in its critical revision. FC and DC share last authorship.
Competing interests MFB has received research funding from Celgene. HvL has acted as a consultant for Celgene, and Eli Lilly and Company, Nordic Pharma Group and Philips, and has received research grants from Amgen, Bayer Schering Pharma, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, MSD, Nordic Pharma Group, Philips and Roche Pharmaceuticals.
Patient consent for publication Not required.
Ethics approval The PANDoRA study protocol was approved by the Ethics Commission of the Medical Faculty of the University of Heidelberg.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The data supporting the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Sharing data will be conditional to approval by the PANDoRA steering committee and, if needed, to additional approval of the competent Institutional Review Boards.
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