A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma-Reference-Cited by-同舟云学术

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

Published:2024-04-12 Issue: Volume: Page:
ISSN:0267-8357
Container-title:Mutagenesis
language:en
Short-container-title:

Author:

Giaccherini Matteo¹^ORCID,Rende Mariaconcetta¹,Gentiluomo Manuel¹^ORCID,Corradi Chiara¹,Archibugi Livia²³,Ermini Stefano⁴,Maiello Evaristo⁵,Morelli Luca⁶,van Eijck Casper H J⁷,Cavestro Giulia Martina⁸,Schneider Marton⁹,Mickevicius Antanas¹⁰,Adamonis Kestutis¹¹,Basso Daniela¹²,Hlavac Viktor¹³,Gioffreda Domenica¹⁴,Talar-Wojnarowska Renata¹⁵,Schöttker Ben¹⁶¹⁷,Lovecek Martin¹⁸,Vanella Giuseppe²³,Gazouli Maria¹⁹^ORCID,Uno Miyuki²⁰,Malecka-Wojciesko Ewa¹⁵,Vodicka Pavel²¹²²^ORCID,Goetz Mara²³,Bijlsma Marteen F²⁴²⁵,Petrone Maria Chiara³,Bazzocchi Francesca²⁶,Kiudelis Mindaugas¹⁰,Szentesi Andrea²⁷²⁸²⁹³⁰,Carrara Silvia³¹,Nappo Gennaro³²³³,Brenner Hermann¹⁶³⁴³⁵,Milanetto Anna Caterina¹²,Soucek Pavel¹³,Katzke Verena³⁶,Peduzzi Giulia¹,Rizzato Cosmeri¹,Pasquali Claudio¹²,Chen Xuechen¹⁶³⁷^ORCID,Capurso Gabriele²³,Hackert Thilo⁹,Bueno-de-Mesquita Bas³⁸^ORCID,Uzunoglu Faik G²³,Hegyi Peter²⁷²⁸²⁹³⁹,Greenhalf William⁴⁰,Theodoropoulos George E⁴¹,Sperti Cosimo¹²,Perri Francesco¹⁴,Oliverius Martin⁴²,Mambrini Andrea⁴³,Tavano Francesca¹⁴,Farinella Riccardo¹,Arcidiacono Paolo Giorgio³,Lucchesi Maurizio⁴³,Bunduc Stefania²⁷²⁹³⁹⁴⁴⁴⁵,Kupcinskas Juozas¹¹,Di Franco Gregorio⁶,Stocker Hannah¹⁶¹⁷,Neoptolemos John P⁹,Bambi Franco⁴,Jamroziak Krzysztof⁴⁶,Testoni Sabrina G G³,Aoki Mateus N⁴⁷,Mohelnikova-Duchonova Beatrice⁴⁸,Izbicki Jacob R²³,Pezzilli Raffaele⁴⁹,Lawlor Rita T⁵⁰,Kauffmann Emanuele F⁵¹,López de Maturana Evangelina⁵²,Malats Nuria⁵²^ORCID,Canzian Federico⁵³^ORCID,Campa Daniele¹^ORCID

Affiliation:

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

Abstract

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.

Funder

Instituto de Salud Carlos III

Lustgarten Foundation & Stand-Up to Cancer

Italian Ministry of Health

Publisher

Oxford University Press (OUP)

Link

https://academic.oup.com/mutage/advance-article-pdf/doi/10.1093/mutage/geae012/57926897/geae012.pdf

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