Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
Zhang, Mingfeng (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Wang, Zhaoming (St. Jude Children's Research Hospital (Memphis, Estats Units d'Amèrica))
Obazee, Ofure (German Cancer Research Center (DKFZ))
Jia, Jinping (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Childs, Erica J. (Johns Hopkins School of Medicine. Department of Oncology)
Hoskins, Jason (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Figlioli, Gisella (German Cancer Research Center (DKFZ))
Mocci, Evelina (Johns Hopkins School of Medicine. Department of Oncology)
Collins, Irene (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Chung, Charles C. (Frederick National Laboratory for Cancer Research (Frederick, Estats Units d'Amèrica))
Hautman, Christopher (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Arslan, Alan A. (New York University Cancer Institute, New York, New York, USA)
Beane-Freeman, Laura (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Bracci, Paige M. (University of California San Francisco. Department of Epidemiology and Biostatistics)
Buring, Julie (Harvard Medical School)
Duell, Eric J. (Institut d'Investigació Biomèdica de Bellvitge)
Gallinger, Steven (Mount Sinai Hospital (Toronto, Canadà))
Giles, Graham G. (Monash University (Melbourne, Austràlia). Department of Epidemiology and Preventive Medicine)
Goodman, Gary E. (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
Goodman, Phyllis J. (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
Kamineni, Aruna (Group Health Research Institute, Seattle, Washington, USA)
Kolonel, Laurence N. (University of Hawaii Cancer Center. Cancer Epidemiology Program)
Kulke, Matthew H. (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica). Department of Medical Oncology)
Malats, Núria (Centro Nacional de Investigaciones Oncológicas)
Olson, Sara H. (Memorial Sloan Kettering Cancer Center)
Sesso, Howard D. (Harvard Medical School)
Visvanathan, Kala (Johns Hopkins Bloomberg School of Public Health)
White, Emily (University of Washington. Department of Epidemiology)
Zheng, Wei (Vanderbilt University Medical Center (Nashville, Estats Units d'Amèrica))
Abnet, Christian C. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Albanes, Demetrius (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Andreotti, Gabriella (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Brais, Lauren (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica). Department of Medical Oncology)
Bueno-de-Mesquita, H. Bas (University of Malaya (Kuala Lumpur, Malàisia). Department of Social & Preventive Medicine)
Basso, Daniela (University Hospital of Padova (Pàdua, Itàlia))
Berndt, Sonja (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Boutron-Ruault, Marie-Christine (IGR, F-94805, Villejuif, France)
Bijlsma, Maarten F. (University of Amsterdam. Laboratory for Experimental Oncology and Radiobiology)
Brenner, Hermann (German Cancer Research Center (DKFZ))
Burdette, Laurie (Frederick National Laboratory for Cancer Research (Frederick, Estats Units d'Amèrica))
Campa, Daniele (University of Pisa (Itàlia). Department of Biology)
Caporaso, Neil E. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Capurso, Gabriele ('Sapienza' University of Rome. Digestive and Liver Disease Unit)
Cavestro, Giulia Martina (Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy)
Cotterchio, Michelle (University of Toronto. Dalla Lana School of Public Health)
Costello, Eithne (University of Liverpool. Liverpool Pancreas Biomedical Research Unit)
Elena, Joanne (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Boggi, Ugo (University Hospital of Pisa (Pisa, Itàlia))
Gaziano, J. Michael (Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA)
Gazouli, Maria (Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece)
Giovannucci, Edward L. (Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA)
Goggins, Michael (Johns Hopkins University. Department of Oncology)
Gross, Myron (Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA)
Haiman, Christopher A. (Preventive Medicine, University of Southern California, Los Angeles, California, USA)
Hassan, Manal (Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA)
Helzlsouer, Kathy J. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Hu, Nan (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Hunter, David J. (Harvard Medical School, Boston, Massachusetts, USA)
Iskierka-Jazdzewska, Elzbieta (Department of Hematology, Medical University of Łodz, Łodz, Poland)
Jenab, Mazda (International Agency for Research on Cancer (IARC), Lyon, France)
Kaaks, Rudolf (German Cancer Research Center (DKFZ))
Key, Timothy J. (Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom)
Khaw, Kay-Tee (School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom)
Klein, Eric A. (Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA)
Kogevinas, M.. (Institut Hospital del Mar d'Investigacions Mèdiques)
Krogh, Vittorio (Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy)
Kupcinskas, Juozas (Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania)
Kurtz, Robert C. (Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA)
Landi, Maria T. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Landi, Stefano (Department of Biology, University of Pisa, Pisa, Italy)
Marchand, Le Loic (Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA)
Mambrini, Andrea (Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy)
Männistö, Satu (National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland)
Milne, Roger L. (Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia)
Neale, Rachel E. (QIMR Berghofer Medical Research Institute (Brisbane, Austràlia))
Oberg, Ann L. (Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA)
Panico, Salvatore (Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy)
Patel, Alpa V. (Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA)
Peeters, Petra H. M. (Imperial College London. Department of Epidemiology and Biostatistics)
Peters, Ulrike (Department of Epidemiology, University of Washington, Seattle, Washington, USA)
Pezzilli, Raffaele (Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy)
Porta, Miquel 1957- (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i Medicina Preventiva i Salut Pública)
Purdue, Mark (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Quiros, J. Ramón (Public Health and Participation Directorate, Asturias, Spain)
Riboli, Elio (Imperial College London. Department of Epidemiology and Biostatistics)
Rothman, Nathaniel (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Scarpa, Aldo (University and Hospital Trust of Verona. ARC-Net Centre for Applied Research on Cancer)
Scelo, Ghislaine (International Agency for Research on Cancer (IARC), Lyon, France)
Shu, Xiao-Ou (Vanderbilt Epidemiology Center (Nashville, Estats Units d'Amèrica))
Silverman, Debra T. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Soucek, Pavel (Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic)
Strobel, Oliver (Heidelberg University Hospital (Alemanya))
Sund, Malin (Umeå University. Department of Surgical and Perioperative Sciences)
Małecka-Panas, Ewa (Medical University of Łodz (Polònia))
Taylor, Philip R. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Tavano, Francesca (Istituto di Ricovero e Cura A Carattere Scientifico (IRCCS))
Travis, Ruth C. (University of Oxford. Cancer Epidemiology Unit)
Thornquist, Mark (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
Tjønneland, Anne (Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark)
Tobias, Geoffrey S. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Trichopoulos, Dimitrios (Hellenic Health Foundation, Athens, Greece)
Vashist, Yogesh (University Hamburg-Eppendorf)
Vodicka, Pavel (Academy of Sciences of the Czech Republic)
Wactawski-Wende, Jean (University at Buffalo. Department of Social and Preventive Medicine)
Wentzensen, Nicolas (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Yu, Herbert (University of Hawaii Cancer Center)
Yu, Kai (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Zeleniuch-Jacquotte, Anne (New York University Cancer Institute)
Kooperberg, Charles (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
Risch, Harvey A. (Yale School of Public Health)
Jacobs, Eric J. (American Cancer Society (Atlanta, Estats Units d'Amèrica))
Li, Donghui (University of Texas M.D. Anderson Cancer Center)
Fuchs, Charles (Brigham and Women's Hospital (Boston, Estats Units d'Amèrica))
Hoover, Robert (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Hartge, Patricia (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Chanock, Stephen (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Petersen, Gloria M. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Stolzenberg-Solomon, Rachael S. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Wolpin, Brian M. (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica). Department of Medical Oncology)
Kraft, Peter (Harvard School of Public Health (Boston, Estats Units d'Amèrica))
Klein, Alison P. (Bloomberg School of Public Health. Department of Epidemiology)
Canzian, Federico (German Cancer Research Center (DKFZ))
Amundadottir, Laufey T. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))

Date:	2016
Abstract:	Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32. 1 (per allele odds ratio (OR) = 1. 20, P = 4. 88×10 −15), rs10094872 at 8q24. 21 (OR = 1. 15, P = 3. 22×10 −9) and rs35226131 at 5p15. 33 (OR = 0. 71, P = 1. 70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32. 1 (NR5A2), chr8q24. 21 (MYC) and chr5p15. 33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32. 1) in the tumors (fold change -7. 6, P = 5. 7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31. 3 to -95. 7, P = 7. 5×10 −4 -2. 0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
Note:	Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Pancreatic cancer ; GWAS ; Fine-mapping ; Imputation ; NR5A2
Published in:	Oncotarget, Vol. 7 (august 2016) , p. 66328-66343, ISSN 1949-2553

DOI: 10.18632/oncotarget.11041
PMID: 27579533

16 p, 3.1 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles