title: Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.
abstract: Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom= 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Capurso
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.|Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pastore
authors.affiliation: Dept of Digestive Tract Diseases, Medical University of Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Talar-Wojnarowska
authors.affiliation: Department of Surgery, Oncology and Gastroenterology (DISCOG), Pancreatic and Digestive Endocrine Surgery, University of Padova, Padova, Italy.
authors.forename: Anna Caterina
authors.initials: AC
authors.lastname: Milanetto
authors.affiliation: Department of Surgery, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Landoni
authors.affiliation: Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Evaristo
authors.initials: E
authors.lastname: Maiello
authors.affiliation: ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.affiliation: Dept of Digestive Tract Diseases, Medical University of Lodz, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Malecka-Panas
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.affiliation: Department of Basic Medical Sciences, Laboratory of Biology, Medical School National and Kapodistrian University of Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Gazouli
authors.affiliation: Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Bonis
authors.affiliation: Mannheim Institute of Transfusion Medicine and Immunology, Heidelberg University, Medical Faculty Mannheim, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Klüter
authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Rinzivillo
authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Delle Fave
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.affiliation: Mannheim Institute of Transfusion Medicine and Immunology, Heidelberg University, Medical Faculty Mannheim, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.affiliation: Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bambi
authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Archibugi
authors.affiliation: ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Katzke
authors.affiliation: Department of Surgery, Konstantopouleion General Hospital Nea Ionia, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Dervenis
authors.affiliation: Department of Surgery, Oncology and Gastroenterology (DISCOG), Pancreatic and Digestive Endocrine Surgery, University of Padova, Padova, Italy.
authors.forename: Valbona
authors.initials: V
authors.lastname: Liço
authors.affiliation: Department of Medicine (DIMED), Laboratory Medicine, University of Padova, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Furlanello
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Strobel
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tavano
authors.affiliation: Department of Medicine (DIMED), Laboratory Medicine, University of Padova, Padova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Basso
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: Department of Surgery, Oncology and Gastroenterology (DISCOG), Pancreatic and Digestive Endocrine Surgery, University of Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquali
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gentiluomo
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Cosmeri
authors.initials: C
authors.lastname: Rizzato
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D019295:Computational Biology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000235:genetics*; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: C000614131:CDKN2A protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18