A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma

Matteo Giaccherini¹, Mariaconcetta Rende¹, Manuel Gentiluomo¹, Chiara Corradi¹, Livia Archibugi^{2

3}, Stefano Ermini⁴, Evaristo Maiello⁵, Luca Morelli⁶, Casper H J van Eijck⁷, Giulia Martina Cavestro⁸, Marton Schneider⁹, Antanas Mickevicius¹⁰, Kestutis Adamonis¹¹, Daniela Basso¹², Viktor Hlavac¹³, Domenica Gioffreda¹⁴, Renata Talar-Wojnarowska¹⁵, Ben Schöttker^{16

17}, Martin Lovecek¹⁸, Giuseppe Vanella^{2

3}, Maria Gazouli¹⁹, Miyuki Uno²⁰, Ewa Malecka-Wojciesko¹⁵, Pavel Vodicka^{21

22}, Mara Goetz²³, Marteen F Bijlsma^{24

25}, Maria Chiara Petrone³, Francesca Bazzocchi²⁶, Mindaugas Kiudelis¹⁰, Andrea Szentesi^{27

28

29

30}, Silvia Carrara³¹, Gennaro Nappo^{32

33}, Hermann Brenner^{16

34

35}, Anna Caterina Milanetto¹², Pavel Soucek¹³, Verena Katzke³⁶, Giulia Peduzzi¹, Cosmeri Rizzato¹, Claudio Pasquali¹², Xuechen Chen^{16

37}, Gabriele Capurso^{2

3}, Thilo Hackert⁹, Bas Bueno-de-Mesquita³⁸, Faik G Uzunoglu²³, Peter Hegyi^{27

28

29

39}, William Greenhalf⁴⁰, George E Theodoropoulos⁴¹, Cosimo Sperti¹², Francesco Perri¹⁴, Martin Oliverius⁴², Andrea Mambrini⁴³, Francesca Tavano¹⁴, Riccardo Farinella¹, Paolo Giorgio Arcidiacono³, Maurizio Lucchesi⁴³, Stefania Bunduc^{27

29

39

44

45}, Juozas Kupcinskas¹¹, Gregorio Di Franco⁶, Hannah Stocker^{16

17}, John P Neoptolemos⁹, Franco Bambi⁴, Krzysztof Jamroziak⁴⁶, Sabrina G G Testoni³, Mateus N Aoki⁴⁷, Beatrice Mohelnikova-Duchonova⁴⁸, Jacob R Izbicki²³, Raffaele Pezzilli⁴⁹, Rita T Lawlor⁵⁰, Emanuele F Kauffmann⁵¹, Evangelina López de Maturana⁵², Nuria Malats⁵², Federico Canzian⁵³, Daniele Campa¹

Affiliations

¹ Department of Biology, University of Pisa, Pisa, Italy.
² Digestive and Liver Disease Unit, Sant'Andrea Hospital, Rome, Italy.
³ Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy.
⁴ Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy.
⁵ Department of Oncology, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
⁶ General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁷ Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁸ Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele, Milan, Italy.
⁹ Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Surgery Department, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹¹ Gastroenterology Department, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹² Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Padua, Italy.
¹³ Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
¹⁴ Division of Gastroenterology and Research Laboratory, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
¹⁵ Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
¹⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany.
¹⁸ Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic.
¹⁹ Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
²⁰ Center for Translational Research in Oncology (LIM24), Instituto Do Câncer Do Estado de São Paulo, (ICESP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil.
²¹ Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic.
²² Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University in Prague, Prague, Czech Republic.
²³ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁴ Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC and Cancer Center Amsterdam, Amsterdam, The Netherlands.
²⁵ Oncode Institute, Amsterdam, The Netherlands.
²⁶ Department of Surgery, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
²⁷ Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary.
²⁸ János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
²⁹ Center for Translational Medicine, Semmelweis University, Budapest, Hungary.
³⁰ Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary.
³¹ Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Milan, Italy.
³² Pancreatic Unit, Humanitas Clinical and Research Center IRCCS, Milan, Italy.
³³ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
³⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
³⁸ Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
³⁹ Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁴⁰ Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
⁴¹ First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁴² Surgery Clinic Third Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴³ Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy.
⁴⁴ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
⁴⁵ Fundeni Clinical Institute, Bucharest, Romania.
⁴⁶ Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
⁴⁷ Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil.
⁴⁸ Department of Oncology, Palacky University Olomouc, Olomouc, Czech Republic.
⁴⁹ County Medical Association of Potenza, Potenza, Italy.
⁵⁰ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
⁵¹ Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy.
⁵² Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 38606763
DOI: 10.1093/mutage/geae012

Meta-Analysis

A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma

Matteo Giaccherini et al. Mutagenesis. 2025.

. 2025 Mar 15;40(1):61-70.

doi: 10.1093/mutage/geae012.

Authors

Affiliations

¹ Department of Biology, University of Pisa, Pisa, Italy.
² Digestive and Liver Disease Unit, Sant'Andrea Hospital, Rome, Italy.
³ Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRSSC San Raffaele Scientific Institute, Milan, Italy.
⁴ Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy.
⁵ Department of Oncology, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
⁶ General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁷ Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁸ Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele, Milan, Italy.
⁹ Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Surgery Department, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹¹ Gastroenterology Department, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹² Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Padua, Italy.
¹³ Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
¹⁴ Division of Gastroenterology and Research Laboratory, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
¹⁵ Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
¹⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany.
¹⁸ Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic.
¹⁹ Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
²⁰ Center for Translational Research in Oncology (LIM24), Instituto Do Câncer Do Estado de São Paulo, (ICESP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil.
²¹ Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic.
²² Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University in Prague, Prague, Czech Republic.
²³ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁴ Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC and Cancer Center Amsterdam, Amsterdam, The Netherlands.
²⁵ Oncode Institute, Amsterdam, The Netherlands.
²⁶ Department of Surgery, Fondazione IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy.
²⁷ Medical School, Institute for Translational Medicine, University of Pécs, Pécs, Hungary.
²⁸ János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
²⁹ Center for Translational Medicine, Semmelweis University, Budapest, Hungary.
³⁰ Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary.
³¹ Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Milan, Italy.
³² Pancreatic Unit, Humanitas Clinical and Research Center IRCCS, Milan, Italy.
³³ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
³⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
³⁸ Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
³⁹ Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁴⁰ Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
⁴¹ First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁴² Surgery Clinic Third Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴³ Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy.
⁴⁴ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
⁴⁵ Fundeni Clinical Institute, Bucharest, Romania.
⁴⁶ Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
⁴⁷ Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil.
⁴⁸ Department of Oncology, Palacky University Olomouc, Olomouc, Czech Republic.
⁴⁹ County Medical Association of Potenza, Potenza, Italy.
⁵⁰ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
⁵¹ Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy.
⁵² Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 38606763
DOI: 10.1093/mutage/geae012

Abstract

Pleiotropic variants (i.e. genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted 10 years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61 052 variants reported to be associated by at least one genome-wide association study with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16 055 pancreatic ductal adenocarcinoma (PDAC) cases and 212 149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P = 6.52 × 10-5) and 7q36.3-rs288762 (P = 3.03 × 10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell-differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Keywords: genetic susceptibility; pancreatic cancer; pleiotropy; single nucleotide polymorphism.

© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma

Affiliations

A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma

Authors

Affiliations

Abstract

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical