Genetic and non-genetic risk factors for early-onset pancreatic cancer

Ylenia Nodari; Manuel Gentiluomo; Beatrice Mohelnikova-Duchonova; Edita Kreivenaite; Anna Caterina Milanetto; Jurgita Skieceviciene; Stefano Landi; Rita T. Lawlor; Maria Chiara Petrone; Paolo Giorgio Arcidiacono; Martin Lovecek; Maria Gazouli; Maarten F. Bijlsma; Luca Morelli; Vytautas Kiudelis; Matteo Tacelli; Dalila Lucíola Zanette; Pavel Soucek; Faik Uzunoglu; Rudolf Kaaks; Jakob Izbicki; Ugo Boggi; Raffaele Pezzilli; Andrea Mambrini; Claudio Pasquali; Hanneke W. van Laarhoven; Verena Katzke; Giulia Martina Cavestro; Cosimo Sperti; Martin Loos; Anna Latiano; Bálint Erőss; Martin Oliverius; Theron Johnson; Daniela Basso; John P. Neoptolemos; Mateus Nóbrega Aoki; William Greenhalf; Pavel Vodicka; Livia Archibugi; Giuseppe Vanella; Maurizio Lucchesi; Renata Talar-Wojnarowska; Krzysztof Jamroziak; Mohammed Al Saeedi; Casper H.J. van Eijck; Juozas Kupcinskas; Tamás Hussein; Marta Puzzono; Stefania Bunduc; Mara Götz; Silvia Carrara; Andrea Szentesi; Francesca Tavano; Stefania Moz; Péter Hegyi; Claudio Luchini; Gabriele Capurso; Francesco Perri; Stefano Ermini; George Theodoropoulos; Giovanni Capretti; Orazio Palmieri; Laura Ginocchi; Niccolò Furbetta; Federico Canzian; Daniele Campa

doi:10.1016/j.dld.2023.02.023

Genetic and non-genetic risk factors for early-onset pancreatic cancer

Ylenia Nodari, Manuel Gentiluomo, Beatrice Mohelnikova-Duchonova, Edita Kreivenaite, Anna Caterina Milanetto, Jurgita Skieceviciene, Stefano Landi, Rita T. Lawlor, Maria Chiara Petrone, Paolo Giorgio Arcidiacono, Martin Lovecek, Maria Gazouli, Maarten F. Bijlsma, Luca Morelli, Vytautas Kiudelis, Matteo Tacelli, Dalila Lucíola Zanette, Pavel Soucek, Faik Uzunoglu, Rudolf KaaksJakob Izbicki, Ugo Boggi, Raffaele Pezzilli, Andrea Mambrini, Claudio Pasquali, Hanneke W. van Laarhoven, Verena Katzke, Giulia Martina Cavestro, Cosimo Sperti, Martin Loos, Anna Latiano, Bálint Erőss, Martin Oliverius, Theron Johnson, Daniela Basso, John P. Neoptolemos, Mateus Nóbrega Aoki, William Greenhalf, Pavel Vodicka, Livia Archibugi, Giuseppe Vanella, Maurizio Lucchesi, Renata Talar-Wojnarowska, Krzysztof Jamroziak, Mohammed Al Saeedi, Casper H.J. van Eijck, Juozas Kupcinskas, Tamás Hussein, Marta Puzzono, Stefania Bunduc, Mara Götz, Silvia Carrara, Andrea Szentesi, Francesca Tavano, Stefania Moz, Péter Hegyi, Claudio Luchini, Gabriele Capurso, Francesco Perri, Stefano Ermini, George Theodoropoulos, Giovanni Capretti, Orazio Palmieri, Laura Ginocchi, Niccolò Furbetta, Federico Canzian, Daniele Campa^*

^*Corresponding author for this work

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Abstract

Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10⁻⁴). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10⁻⁴). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Original language	English
Pages (from-to)	1417-1425
Number of pages	9
Journal	Digestive and Liver Disease
Volume	55
Issue number	10
DOIs	https://doi.org/10.1016/j.dld.2023.02.023
Publication status	Published - Oct 2023

Bibliographical note

Funding Information:
This study was supported by Fondazione Arpa and Fondazione Tizzi (to Daniele Campa); Inter-COST project no. LTC19015 provided by the Ministry of Education Youth and Sports of the Czech Republic (to Pavel Soucek); the Czech Health Research Council, project no.: NV19-03-00097 (to Beatrice Mohelnikova-Duchonova); the Italian Ministry of Health grants (Ricerca Corrente 2018-2021) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5 × 1000″ voluntary contribution. The EPIC-Oxford study has received funding from Cancer Research UK (C8221/A19170 and C8221/A29017) and the Medical Research Council (MR/M012190/1). The research leading to these results has received funding from AIRC under IG 2021 - ID. 26201 project – P.I. Gabriele Capurso. This article is based upon work from COST Action TRANSPAN, CA21116, supported by COST (European Cooperation in Science and Technology).

Funding Information:
This research used genotyping data provided to the PANDoRA consortium by the EPIC cohort, for which we would like to thank the contributors from EPIC UK and EPIC NL. We are grateful to all the participants who have been part of the project and to Prof. Vermeulen R.C.H. (University of Utrecht) for the EPIC genotyping data. Pavel Vodicka acknowledges projects NU21-07-00247 and Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund.

Publisher Copyright:
© 2023 Editrice Gastroenterologica Italiana S.r.l.

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1-s2.0-S1590865823005145-mainFinal published version, 1.09 MBLicence: CC BY-NC-ND

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Nodari, Y., Gentiluomo, M., Mohelnikova-Duchonova, B., Kreivenaite, E., Milanetto, A. C., Skieceviciene, J., Landi, S., Lawlor, R. T., Petrone, M. C., Arcidiacono, P. G., Lovecek, M., Gazouli, M., Bijlsma, M. F., Morelli, L., Kiudelis, V., Tacelli, M., Zanette, D. L., Soucek, P., Uzunoglu, F., ... Campa, D. (2023). Genetic and non-genetic risk factors for early-onset pancreatic cancer. Digestive and Liver Disease, 55(10), 1417-1425. https://doi.org/10.1016/j.dld.2023.02.023

@article{a96c0fc0eb08405fbf2af59d50640a72,

title = "Genetic and non-genetic risk factors for early-onset pancreatic cancer",

abstract = "Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.",

author = "Ylenia Nodari and Manuel Gentiluomo and Beatrice Mohelnikova-Duchonova and Edita Kreivenaite and Milanetto, {Anna Caterina} and Jurgita Skieceviciene and Stefano Landi and Lawlor, {Rita T.} and Petrone, {Maria Chiara} and Arcidiacono, {Paolo Giorgio} and Martin Lovecek and Maria Gazouli and Bijlsma, {Maarten F.} and Luca Morelli and Vytautas Kiudelis and Matteo Tacelli and Zanette, {Dalila Luc{\'i}ola} and Pavel Soucek and Faik Uzunoglu and Rudolf Kaaks and Jakob Izbicki and Ugo Boggi and Raffaele Pezzilli and Andrea Mambrini and Claudio Pasquali and {van Laarhoven}, {Hanneke W.} and Verena Katzke and Cavestro, {Giulia Martina} and Cosimo Sperti and Martin Loos and Anna Latiano and B{\'a}lint Er{\H o}ss and Martin Oliverius and Theron Johnson and Daniela Basso and Neoptolemos, {John P.} and Aoki, {Mateus N{\'o}brega} and William Greenhalf and Pavel Vodicka and Livia Archibugi and Giuseppe Vanella and Maurizio Lucchesi and Renata Talar-Wojnarowska and Krzysztof Jamroziak and Saeedi, {Mohammed Al} and {van Eijck}, {Casper H.J.} and Juozas Kupcinskas and Tam{\'a}s Hussein and Marta Puzzono and Stefania Bunduc and Mara G{\"o}tz and Silvia Carrara and Andrea Szentesi and Francesca Tavano and Stefania Moz and P{\'e}ter Hegyi and Claudio Luchini and Gabriele Capurso and Francesco Perri and Stefano Ermini and George Theodoropoulos and Giovanni Capretti and Orazio Palmieri and Laura Ginocchi and Niccol{\`o} Furbetta and Federico Canzian and Daniele Campa",

note = "Funding Information: This study was supported by Fondazione Arpa and Fondazione Tizzi (to Daniele Campa); Inter-COST project no. LTC19015 provided by the Ministry of Education Youth and Sports of the Czech Republic (to Pavel Soucek); the Czech Health Research Council, project no.: NV19-03-00097 (to Beatrice Mohelnikova-Duchonova); the Italian Ministry of Health grants (Ricerca Corrente 2018-2021) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5 × 1000″ voluntary contribution. The EPIC-Oxford study has received funding from Cancer Research UK (C8221/A19170 and C8221/A29017) and the Medical Research Council (MR/M012190/1). The research leading to these results has received funding from AIRC under IG 2021 - ID. 26201 project – P.I. Gabriele Capurso. This article is based upon work from COST Action TRANSPAN, CA21116, supported by COST (European Cooperation in Science and Technology). Funding Information: This research used genotyping data provided to the PANDoRA consortium by the EPIC cohort, for which we would like to thank the contributors from EPIC UK and EPIC NL. We are grateful to all the participants who have been part of the project and to Prof. Vermeulen R.C.H. (University of Utrecht) for the EPIC genotyping data. Pavel Vodicka acknowledges projects NU21-07-00247 and Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund. Publisher Copyright: {\textcopyright} 2023 Editrice Gastroenterologica Italiana S.r.l.",

year = "2023",

month = oct,

doi = "10.1016/j.dld.2023.02.023",

language = "English",

volume = "55",

pages = "1417--1425",

journal = "Digestive and Liver Disease",

issn = "1590-8658",

publisher = "Elsevier",

number = "10",

}

Nodari, Y, Gentiluomo, M, Mohelnikova-Duchonova, B, Kreivenaite, E, Milanetto, AC, Skieceviciene, J, Landi, S, Lawlor, RT, Petrone, MC, Arcidiacono, PG, Lovecek, M, Gazouli, M, Bijlsma, MF, Morelli, L, Kiudelis, V, Tacelli, M, Zanette, DL, Soucek, P, Uzunoglu, F, Kaaks, R, Izbicki, J, Boggi, U, Pezzilli, R, Mambrini, A, Pasquali, C, van Laarhoven, HW, Katzke, V, Cavestro, GM, Sperti, C, Loos, M, Latiano, A, Erőss, B, Oliverius, M, Johnson, T, Basso, D, Neoptolemos, JP, Aoki, MN, Greenhalf, W, Vodicka, P, Archibugi, L, Vanella, G, Lucchesi, M, Talar-Wojnarowska, R, Jamroziak, K, Saeedi, MA, van Eijck, CHJ, Kupcinskas, J, Hussein, T, Puzzono, M, Bunduc, S, Götz, M, Carrara, S, Szentesi, A, Tavano, F, Moz, S, Hegyi, P, Luchini, C, Capurso, G, Perri, F, Ermini, S, Theodoropoulos, G, Capretti, G, Palmieri, O, Ginocchi, L, Furbetta, N, Canzian, F & Campa, D 2023, 'Genetic and non-genetic risk factors for early-onset pancreatic cancer', Digestive and Liver Disease, vol. 55, no. 10, pp. 1417-1425. https://doi.org/10.1016/j.dld.2023.02.023

TY - JOUR

T1 - Genetic and non-genetic risk factors for early-onset pancreatic cancer

AU - Nodari, Ylenia

AU - Gentiluomo, Manuel

AU - Mohelnikova-Duchonova, Beatrice

AU - Kreivenaite, Edita

AU - Milanetto, Anna Caterina

AU - Skieceviciene, Jurgita

AU - Landi, Stefano

AU - Lawlor, Rita T.

AU - Petrone, Maria Chiara

AU - Arcidiacono, Paolo Giorgio

AU - Lovecek, Martin

AU - Gazouli, Maria

AU - Bijlsma, Maarten F.

AU - Morelli, Luca

AU - Kiudelis, Vytautas

AU - Tacelli, Matteo

AU - Zanette, Dalila Lucíola

AU - Soucek, Pavel

AU - Uzunoglu, Faik

AU - Kaaks, Rudolf

AU - Izbicki, Jakob

AU - Boggi, Ugo

AU - Pezzilli, Raffaele

AU - Mambrini, Andrea

AU - Pasquali, Claudio

AU - van Laarhoven, Hanneke W.

AU - Katzke, Verena

AU - Cavestro, Giulia Martina

AU - Sperti, Cosimo

AU - Loos, Martin

AU - Latiano, Anna

AU - Erőss, Bálint

AU - Oliverius, Martin

AU - Johnson, Theron

AU - Basso, Daniela

AU - Neoptolemos, John P.

AU - Aoki, Mateus Nóbrega

AU - Greenhalf, William

AU - Vodicka, Pavel

AU - Archibugi, Livia

AU - Vanella, Giuseppe

AU - Lucchesi, Maurizio

AU - Talar-Wojnarowska, Renata

AU - Jamroziak, Krzysztof

AU - Saeedi, Mohammed Al

AU - van Eijck, Casper H.J.

AU - Kupcinskas, Juozas

AU - Hussein, Tamás

AU - Puzzono, Marta

AU - Bunduc, Stefania

AU - Götz, Mara

AU - Carrara, Silvia

AU - Szentesi, Andrea

AU - Tavano, Francesca

AU - Moz, Stefania

AU - Hegyi, Péter

AU - Luchini, Claudio

AU - Capurso, Gabriele

AU - Perri, Francesco

AU - Ermini, Stefano

AU - Theodoropoulos, George

AU - Capretti, Giovanni

AU - Palmieri, Orazio

AU - Ginocchi, Laura

AU - Furbetta, Niccolò

AU - Canzian, Federico

AU - Campa, Daniele

N1 - Funding Information: This study was supported by Fondazione Arpa and Fondazione Tizzi (to Daniele Campa); Inter-COST project no. LTC19015 provided by the Ministry of Education Youth and Sports of the Czech Republic (to Pavel Soucek); the Czech Health Research Council, project no.: NV19-03-00097 (to Beatrice Mohelnikova-Duchonova); the Italian Ministry of Health grants (Ricerca Corrente 2018-2021) to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5 × 1000″ voluntary contribution. The EPIC-Oxford study has received funding from Cancer Research UK (C8221/A19170 and C8221/A29017) and the Medical Research Council (MR/M012190/1). The research leading to these results has received funding from AIRC under IG 2021 - ID. 26201 project – P.I. Gabriele Capurso. This article is based upon work from COST Action TRANSPAN, CA21116, supported by COST (European Cooperation in Science and Technology). Funding Information: This research used genotyping data provided to the PANDoRA consortium by the EPIC cohort, for which we would like to thank the contributors from EPIC UK and EPIC NL. We are grateful to all the participants who have been part of the project and to Prof. Vermeulen R.C.H. (University of Utrecht) for the EPIC genotyping data. Pavel Vodicka acknowledges projects NU21-07-00247 and Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life, IMTS: 313011V446, co-financed by the European Regional Development Fund. Publisher Copyright: © 2023 Editrice Gastroenterologica Italiana S.r.l.

PY - 2023/10

Y1 - 2023/10

N2 - Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

AB - Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

UR - http://www.scopus.com/inward/record.url?scp=85151481167&partnerID=8YFLogxK

U2 - 10.1016/j.dld.2023.02.023

DO - 10.1016/j.dld.2023.02.023

M3 - Article

C2 - 36973108

AN - SCOPUS:85151481167

SN - 1590-8658

VL - 55

SP - 1417

EP - 1425

JO - Digestive and Liver Disease

JF - Digestive and Liver Disease

IS - 10

ER -

Genetic and non-genetic risk factors for early-onset pancreatic cancer

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Bibliographical note

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