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 Basso; Cosimo 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

doi:https://doi.org/10.1136/jmedgenet-2020-106961

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 journal › Article › Academic › peer-review

30 Citations (Scopus)

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 language	English
Pages (from-to)	369-377
Number of pages	9
Journal	Journal of medical genetics
Volume	58
Issue number	6
Early online date	2020
DOIs	https://doi.org/10.1136/jmedgenet-2020-106961
Publication status	Published - 1 Jun 2021

Keywords

genetic epidemiology
oncology
pancreas and biliary tract

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https://doi.org/10.1136/jmedgenet-2020-106961

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Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schöttker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., ... Campa, D. (2021). Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction. Journal of medical genetics, 58(6), 369-377. https://doi.org/10.1136/jmedgenet-2020-106961

@article{83a5c2813dcf4939adeb8a3ba022dedd,

title = "Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction",

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.",

keywords = "genetic epidemiology, oncology, pancreas and biliary tract",

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

note = "Funding Information: Funding This work was partially supported by Fondazione Arpa (www. fondazionearpa.it) and by Fondazione Tizzi (www.fondazionetizzi.it). Funding Information: 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. Publisher Copyright: {\textcopyright} 2021 American Institute of Physics Inc.. All rights reserved.",

year = "2021",

month = jun,

day = "1",

doi = "https://doi.org/10.1136/jmedgenet-2020-106961",

language = "English",

volume = "58",

pages = "369--377",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "6",

}

Galeotti, AA, Gentiluomo, M, Rizzato, C, Obazee, O, Neoptolemos, JP, Pasquali, C, Nentwich, M, Cavestro, GM, Pezzilli, R, Greenhalf, W, Holleczek, B, Schroeder, C, Schöttker, B, Ivanauskas, A, Ginocchi, L, Key, TJ, Hegyi, P, Archibugi, L, Darvasi, E, Basso, D, Sperti, C, Bijlsma, MF, Palmieri, O, Hlavac, V, Talar-Wojnarowska, R, Mohelnikova-Duchonova, B, Hackert, T, Vashist, Y, Strouhal, O, Van Laarhoven, H, Tavano, F, Lovecek, M, Dervenis, C, Izbéki, F, Padoan, A, Małecka-Panas, E, Maiello, E, Vanella, G, Capurso, G, Izbicki, JR, Theodoropoulos, GE, Jamroziak, K, Katzke, V, Kaaks, R, Mambrini, A, Papanikolaou, IS, Szmola, R, Szentesi, A, Kupcinskas, J, Bursi, S, Costello, E, Boggi, U, Milanetto, AC, Landi, S, Gazouli, M, Vodickova, L, Soucek, P, Gioffreda, D, Gemignani, F, Brenner, H, Strobel, O, Büchler, M, Vodicka, P, Paiella, S, Canzian, F & Campa, D 2021, 'Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction', Journal of medical genetics, vol. 58, no. 6, pp. 369-377. https://doi.org/10.1136/jmedgenet-2020-106961

TY - JOUR

T1 - Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

AU - Galeotti, Alice Alessandra

AU - Gentiluomo, Manuel

AU - Rizzato, Cosmeri

AU - Obazee, Ofure

AU - Neoptolemos, John P.

AU - Pasquali, Claudio

AU - Nentwich, Michael

AU - Cavestro, Giulia Martina

AU - Pezzilli, Raffaele

AU - Greenhalf, William

AU - Holleczek, Bernd

AU - Schroeder, Cornelia

AU - Schöttker, Ben

AU - Ivanauskas, Audrius

AU - Ginocchi, Laura

AU - Key, Timothy J.

AU - Hegyi, Péter

AU - Archibugi, Livia

AU - Darvasi, Erika

AU - Basso, Daniela

AU - Sperti, Cosimo

AU - Bijlsma, Maarten F.

AU - Palmieri, Orazio

AU - Hlavac, Viktor

AU - Talar-Wojnarowska, Renata

AU - Mohelnikova-Duchonova, Beatrice

AU - Hackert, Thilo

AU - Vashist, Yogesh

AU - Strouhal, Ondrej

AU - Van Laarhoven, Hanneke

AU - Tavano, Francesca

AU - Lovecek, Martin

AU - Dervenis, Christos

AU - Izbéki, Ferenc

AU - Padoan, Andrea

AU - Małecka-Panas, Ewa

AU - Maiello, Evaristo

AU - Vanella, Giuseppe

AU - Capurso, Gabriele

AU - Izbicki, Jakob R.

AU - Theodoropoulos, George E.

AU - Jamroziak, Krzysztof

AU - Katzke, Verena

AU - Kaaks, Rudolf

AU - Mambrini, Andrea

AU - Papanikolaou, Ioannis S.

AU - Szmola, Richárd

AU - Szentesi, Andrea

AU - Kupcinskas, Juozas

AU - Bursi, Simona

AU - Costello, Eithne

AU - Boggi, Ugo

AU - Milanetto, Anna Caterina

AU - Landi, Stefano

AU - Gazouli, Maria

AU - Vodickova, Ludmila

AU - Soucek, Pavel

AU - Gioffreda, Domenica

AU - Gemignani, Federica

AU - Brenner, Hermann

AU - Strobel, Oliver

AU - Büchler, Markus

AU - Vodicka, Pavel

AU - Paiella, Salvatore

AU - Canzian, Federico

AU - Campa, Daniele

N1 - Funding Information: Funding This work was partially supported by Fondazione Arpa (www. fondazionearpa.it) and by Fondazione Tizzi (www.fondazionetizzi.it). Funding Information: 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. Publisher Copyright: © 2021 American Institute of Physics Inc.. All rights reserved.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

KW - genetic epidemiology

KW - oncology

KW - pancreas and biliary tract

UR - http://www.scopus.com/inward/record.url?scp=85092010656&partnerID=8YFLogxK

U2 - https://doi.org/10.1136/jmedgenet-2020-106961

DO - https://doi.org/10.1136/jmedgenet-2020-106961

M3 - Article

C2 - 32591343

SN - 0022-2593

VL - 58

SP - 369

EP - 377

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 6

ER -

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

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