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Research Papers:

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

Daniele Campa _, Manuela Pastore, Manuel Gentiluomo, Renata Talar-Wojnarowska, Juozas Kupcinskas, Ewa Malecka-Panas, John P. Neoptolemos, Willem Niesen, Pavel Vodicka, Gianfranco Delle Fave, H. Bas Bueno-de-Mesquita, Maria Gazouli, Paola Pacetti, Milena Di Leo, Hidemi Ito, Harald Klüter, Pavel Soucek, Vincenzo Corbo, Kenji Yamao, Satoyo Hosono, Rudolf Kaaks, Yogesh Vashist, Domenica Gioffreda, Oliver Strobel, Yasuhiro Shimizu, Frederike Dijk, Angelo Andriulli, Audrius Ivanauskas, Peter Bugert, Francesca Tavano, Ludmila Vodickova, Carlo Federico Zambon, Martin Lovecek, Stefano Landi, Timothy J. Key, Ugo Boggi, Raffaele Pezzilli, Krzysztof Jamroziak, Beatrice Mohelnikova-Duchonova, Andrea Mambrini, Franco Bambi, Olivier Busch, Valerio Pazienza, Roberto Valente, George E. Theodoropoulos, Thilo Hackert, Gabriele Capurso, Giulia Martina Cavestro, Claudio Pasquali, Daniela Basso, Cosimo Sperti, Keitaro Matsuo, Markus Büchler, Kay-Tee Khaw, Jakob Izbicki, Eithne Costello, Verena Katzke, Christoph Michalski, Anna Stepien, Cosmeri Rizzato and Federico Canzian

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Oncotarget. 2016; 7:57011-57020. https://doi.org/10.18632/oncotarget.10935

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Abstract

Daniele Campa1,2, Manuela Pastore1,2, Manuel Gentiluomo1,2, Renata Talar-Wojnarowska3, Juozas Kupcinskas4, Ewa Malecka-Panas3, John P. Neoptolemos5, Willem Niesen6, Pavel Vodicka7,8, Gianfranco Delle Fave9, H. Bas Bueno-de-Mesquita10,11,12, Maria Gazouli13, Paola Pacetti14, Milena Di Leo15, Hidemi Ito16, Harald Klüter17, Pavel Soucek18,19, Vincenzo Corbo20, Kenji Yamao21, Satoyo Hosono16, Rudolf Kaaks22, Yogesh Vashist23, Domenica Gioffreda24, Oliver Strobel6, Yasuhiro Shimizu25, Frederike Dijk26, Angelo Andriulli24, Audrius Ivanauskas4, Peter Bugert17, Francesca Tavano24, Ludmila Vodickova8,27, Carlo Federico Zambon28, Martin Lovecek29, Stefano Landi1, Timothy J. Key30, Ugo Boggi31, Raffaele Pezzilli32, Krzysztof Jamroziak33, Beatrice Mohelnikova-Duchonova18,34, Andrea Mambrini14, Franco Bambi35, Olivier Busch36, Valerio Pazienza24, Roberto Valente9, George E. Theodoropoulos37, Thilo Hackert6, Gabriele Capurso9, Giulia Martina Cavestro15, Claudio Pasquali38, Daniela Basso39, Cosimo Sperti38, Keitaro Matsuo40, Markus Büchler6, Kay-Tee Khaw41, Jakob Izbicki23, Eithne Costello5, Verena Katzke22, Christoph Michalski6, Anna Stepien42, Cosmeri Rizzato43, Federico Canzian2

1Department of Biology, University of Pisa, Pisa, Italy

2Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

3Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland

4Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania

5Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom

6Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

7Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic

8Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic

9Digestive and Liver Disease Unit, S. Andrea Hospital, ‘Sapienza’ University of Rome, Rome, Italy

10Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

11Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom

12Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

13Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

14Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest, Carrara, Italy

15Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy

16Division Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

17Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg – Hessen gGmbH, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

18Laboratory of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic

19Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic

20ARC-Net Research Centre, and Department of Diagnostics and Public Health University and Hospital Trust of Verona, Verona, Italy

21Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan

22Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

23Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

24Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

25Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

26Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands

27Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic

28Department of Medicine - DIMED, University of Padova, Padova, Italy

29Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic

30Epidemiology Unit Nuffield Department of Population Health University of Oxford, Oxford, UK

31Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy

32Pancreas Unit, Department of Digestive System, Dant’Orsola-Malpighi Hospital, Bologna, Italy

33Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland

34Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic

35Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy

36Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands

37Colorectal Unit, First Department of Propaedeutic Surgery, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece

38Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Padova, Italy

39Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy

40Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan

41Clinical Gerontology Unit, Addenbrooke’s Hospital, School of Clinical Medicine, University of Cambridge, Cambridge, UK

42Laboratory of Clinical, Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland

43Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

Correspondence to:

Federico Canzian, email: f.canzian@dkfz.de

Keywords: pancreatic cancer, CDKN2A, single nucleotide polymorphisms, miRSNP, association study

Received: May 09, 2016    Accepted: July 13, 2016    Published: July 29, 2016

ABSTRACT

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.


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