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

Campa D 1 , Pastore M 1 , Gentiluomo M 1 , Talar-Wojnarowska R 2 , Kupcinskas J 3 , Malecka-Panas E 2 Show all authors , Neoptolemos JP 4 , Niesen W 5 , Vodicka P 6 , Delle Fave G 7 , Bueno-de-Mesquita HB 8 , Gazouli M 9 , Pacetti P 10 , Di Leo M 11 , Ito H 12 , Klüter H 13 , Soucek P 14 , Corbo V 15 , Yamao K 16 , Hosono S 12 , Kaaks R 17 , Vashist Y 18 , Gioffreda D 19 , Strobel O 5 , Shimizu Y 20 , Dijk F 21 , Andriulli A 19 , Ivanauskas A 3 , Bugert P 13 , Tavano F 19 , Vodickova L 22 , Zambon CF 23 , Lovecek M 24 , Landi S 1 , Key TJ 25 , Boggi U 26 , Pezzilli R 27 , Jamroziak K 28 , Mohelnikova-Duchonova B 14 , Mambrini A 10 , Bambi F 29 , Busch O 30 , Pazienza V 19 , Valente R 7 , Theodoropoulos GE 31 , Hackert T 5 , Capurso G 7 , Cavestro GM 11 , Pasquali C 32 , Basso D 33 , Sperti C 32 , Matsuo K 34 , Büchler M 5 , Khaw KT 35 , Izbicki J 18 , Costello E 4 , Katzke V 17 , Michalski C 5 , Stepien A 36 , Rizzato C 37 , Canzian F 38

Affiliations 

  • 1 Department of Biology, University of Pisa, Pisa, Italy
  • 2 Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
  • 3 Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
  • 4 Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom
  • 5 Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
  • 6 Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic
  • 7 Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy
  • 8 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 9 Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • 10 Oncological Department Massa Carrara Azienda USL Toscana Nord Ovest, Carrara, Italy
  • 11 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 12 Division Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 13 Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 14 Laboratory of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic
  • 15 ARC-Net Research Centre, and Department of Diagnostics and Public Health University and Hospital Trust of Verona, Verona, Italy
  • 16 Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
  • 17 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 18 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 19 Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
  • 20 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
  • 21 Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands
  • 22 Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
  • 23 Department of Medicine - DIMED, University of Padova, Padova, Italy
  • 24 Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
  • 25 Epidemiology Unit Nuffield Department of Population Health University of Oxford, Oxford, UK
  • 26 Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
  • 27 Pancreas Unit, Department of Digestive System, Dant'Orsola-Malpighi Hospital, Bologna, Italy
  • 28 Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
  • 29 Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy
  • 30 Department of Surgery, Academic Medical Centre, Amsterdam, The Netherlands
  • 31 Colorectal Unit, First Department of Propaedeutic Surgery, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • 32 Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Padova, Italy
  • 33 Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
  • 34 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 35 Clinical Gerontology Unit, Addenbrooke’s Hospital, School of Clinical Medicine, University of Cambridge, Cambridge, UK
  • 36 Laboratory of Clinical, Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland
  • 37 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
  • 38 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
Oncotarget, 2016 08 30;7(35):57011-57020.
PMID: 27486979 DOI: 10.18632/oncotarget.10935

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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