Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Alice Alessandra Galeotti, Manuel Gentiluomo, Cosmeri Rizzato, Ofure Obazee, John P. Neoptolemos, Claudio Pasquali, Michael Nentwich, Giulia Martina Cavestro, Raffaele Pezzilli, William Greenhalf, Bernd Holleczek, Cornelia Schroeder, Ben Schöttker, Audrius Ivanauskas, Laura Ginocchi, Timothy J. Key, Péter Hegyi, Livia Archibugi, Erika Darvasi, Daniela BassoCosimo Sperti, Maarten F. Bijlsma, Orazio Palmieri, Viktor Hlavac, Renata Talar-Wojnarowska, Beatrice Mohelnikova-Duchonova, Thilo Hackert, Yogesh Vashist, Ondrej Strouhal, Hanneke Van Laarhoven, Francesca Tavano, Martin Lovecek, Christos Dervenis, Ferenc Izbéki, Andrea Padoan, Ewa Małecka-Panas, Evaristo Maiello, Giuseppe Vanella, Gabriele Capurso, Jakob R. Izbicki, George E. Theodoropoulos, Krzysztof Jamroziak, Verena Katzke, Rudolf Kaaks, Andrea Mambrini, Ioannis S. Papanikolaou, Richárd Szmola, Andrea Szentesi, Juozas Kupcinskas, Simona Bursi, Eithne Costello, Ugo Boggi, Anna Caterina Milanetto, Stefano Landi, Maria Gazouli, Ludmila Vodickova, Pavel Soucek, Domenica Gioffreda, Federica Gemignani, Hermann Brenner, Oliver Strobel, Markus Büchler, Pavel Vodicka, Salvatore Paiella, Federico Canzian, Daniele Campa

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalJournal of Medical Genetics
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • genetic epidemiology
  • oncology
  • pancreas and biliary tract

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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