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Oncotarget. 2016 Oct 11;7(41):66328-66343. doi: 10.18632/oncotarget.11041.

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Zhang M1, Wang Z2,3,4, Obazee O5, Jia J1, Childs EJ6, Hoskins J1, Figlioli G5, Mocci E6, Collins I1, Chung CC2,3, Hautman C1, Arslan AA7,8,9, Beane-Freeman L2, Bracci PM10, Buring J11,12, Duell EJ13, Gallinger S14, Giles GG15,16,17, Goodman GE18, Goodman PJ19, Kamineni A20, Kolonel LN21, Kulke MH22, Malats N23, Olson SH24, Sesso HD25,11,12, Visvanathan K26, White E18,27, Zheng W28,29, Abnet CC2, Albanes D2, Andreotti G2, Brais L22, Bueno-de-Mesquita HB30,31,32, Basso D33, Berndt SI2, Boutron-Ruault MC34,35,36, Bijlsma MF37, Brenner H38,39,40, Burdette L2,3, Campa D41, Caporaso NE2, Capurso G42, Cavestro GM43, Cotterchio M44,45, Costello E46, Elena J47, Boggi U48, Gaziano JM11,12,49, Gazouli M50, Giovannucci EL25,51,52, Goggins M53,54,55, Gross M56, Haiman CA57, Hassan M58, Helzlsouer KJ47, Hu N2, Hunter DJ59,60,61, Iskierka-Jazdzewska E62, Jenab M63, Kaaks R64, Key TJ65, Khaw KT66, Klein EA67, Kogevinas M68,69,70, Krogh V71, Kupcinskas J72, Kurtz RC73, Landi MT2, Landi S41, Le Marchand L21, Mambrini A74, Mannisto S75, Milne RL15,16, Neale RE76, Oberg AL77, Panico S78, Patel AV79, Peeters PH80,31, Peters U18,27, Pezzilli R81, Porta M69,82,83, Purdue M2, Quiros JR84, Riboli E31, Rothman N2, Scarpa A85, Scelo G63, Shu XO28,29, Silverman DT2, Soucek P86, Strobel O87, Sund M88, Małecka-Panas E89, Taylor PR2, Tavano F90, Travis RC65, Thornquist M18, Tjønneland A91, Tobias GS2, Trichopoulos D25,92,93, Vashist Y94, Vodicka P95, Wactawski-Wende J96, Wentzensen N2, Yu H21, Yu K2, Zeleniuch-Jacquotte A8,97, Kooperberg C98, Risch HA99, Jacobs EJ79, Li D58, Fuchs C22,51, Hoover R2, Hartge P2, Chanock SJ2, Petersen GM100, Stolzenberg-Solomon RS2, Wolpin BM22, Kraft P25,101, Klein AP6,102, Canzian F5, Amundadottir LT1.

Author information

1
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
3
Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
4
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
7
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA.
8
Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.
9
New York University Cancer Institute, New York, New York, USA,.
10
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
11
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
12
Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
13
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain.
14
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
15
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
16
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
17
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
18
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
19
Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
20
Group Health Research Institute, Seattle, Washington, USA,.
21
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
22
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
23
Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
24
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
25
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
26
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
27
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
28
Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
29
Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
30
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
31
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
32
Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
33
Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,.
34
Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France.
35
University Paris Sud, UMRS 1018, F-94805, Villejuif, France.
36
IGR, F-94805, Villejuif, France.
37
Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
38
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
39
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
40
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
41
Department of Biology, University of Pisa, Pisa, Italy.
42
Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy.
43
Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
44
Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
45
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
46
National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
47
Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
48
Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
49
Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.
50
Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
51
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
52
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
53
Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
54
Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
55
Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
56
Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
57
Preventive Medicine, University of Southern California, Los Angeles, California, USA.
58
Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
59
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
60
Harvard School of Public Health, Boston, Massachusetts, USA.
61
Harvard Medical School, Boston, Massachusetts, USA.
62
Department of Hematology, Medical University of Łodz, Łodz, Poland.
63
International Agency for Research on Cancer (IARC), Lyon, France.
64
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
65
Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
66
School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
67
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.
68
Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
69
Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain.
70
National School of Public Health, Athens, Greece.
71
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
72
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
73
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
74
Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
75
National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland.
76
Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
77
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
78
Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy.
79
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
80
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
81
Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
82
School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
83
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
84
Public Health and Participation Directorate, Asturias, Spain.
85
ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
86
Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
87
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
88
Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden.
89
Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
90
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
91
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
92
Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.
93
Hellenic Health Foundation, Athens, Greece.
94
Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany.
95
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
96
Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA.
97
New York University Cancer Institute, New York, New York, USA.
98
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,.
99
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
100
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
101
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
102
Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA.

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 = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -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 = 5.7x10 -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 = 7.5x10 -4-2.0x10 -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.

KEYWORDS:

GWAS; NR5A2 ; fine-mapping; imputation; pancreatic cancer

PMID:
27579533
PMCID:
PMC5340084
DOI:
10.18632/oncotarget.11041
[Indexed for MEDLINE]
Free PMC Article

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