TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.
A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Daniele
D
Campa
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cosmeri
C
Rizzato
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Rachael
R
Stolzenberg-Solomon
Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
Paola
P
Pacetti
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic.
Pavel
P
Vodicka
Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
Sean P
SP
Cleary
Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
Gabriele
G
Capurso
Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.|Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
H B As
HB
Bueno-de-Mesquita
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Jens
J
Werner
Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
Maria
M
Gazouli
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Katja
K
Butterbach
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Audrius
A
Ivanauskas
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Nathalia
N
Giese
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN.
Gloria M
GM
Petersen
Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy.
Paola
P
Fogar
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Zhaoming
Z
Wang
Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy.
Claudio
C
Bassi
Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic.
Miroslav
M
Ryska
1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece.
George E
GE
Theodoropoulos
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Charles
C
Kooperberg
Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Donghui
D
Li
National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
William
W
Greenhalf
Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy.
Claudio
C
Pasquali
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Thilo
T
Hackert
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Charles S
CS
Fuchs
Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic.
Beatrice
B
Mohelnikova-Duchonova
Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy.
Cosimo
C
Sperti
Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
Niccola
N
Funel
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
Aida Karina
AK
Dieffenbach
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Nicholas J
NJ
Wareham
Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Julie
J
Buring
Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Ivana
I
Holcátová
National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
Eithne
E
Costello
Department of Medicine - DIMED, University of Padua, Padua, Italy.
Carlo-Federico
CF
Zambon
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Juozas
J
Kupcinskas
Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT.
Harvey A
HA
Risch
Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Peter
P
Kraft
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
Paige M
PM
Bracci
Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
Raffaele
R
Pezzilli
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
Sara H
SH
Olson
Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Howard D
HD
Sesso
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Patricia
P
Hartge
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Oliver
O
Strobel
Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
Ewa
E
Małecka-Panas
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
Kala
K
Visvanathan
Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY.
Alan A
AA
Arslan
Surgical Clinic 4, University of Padua, Padua, Italy.
Sergio
S
Pedrazzoli
Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.
Pavel
P
Souček
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy.
Domenica
D
Gioffreda
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
Timothy J
TJ
Key
Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
Renata
R
Talar-Wojnarowska
ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
Aldo
A
Scarpa
Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
Andrea
A
Mambrini
Epidemiology Research Program, American Cancer Society, Atlanta, GA.
Eric J
EJ
Jacobs
Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
Krzysztof
K
Jamroziak
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
Alison
A
Klein
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy.
Francesca
F
Tavano
Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy.
Franco
F
Bambi
Department of Biology, University of Pisa, Pisa, Italy.
Stefano
S
Landi
Department of Epidemiology, University of Washington, Seattle, WA.
Melissa A
MA
Austin
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic.
Ludmila
L
Vodickova
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
Hermann
H
Brenner
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Stephen J
SJ
Chanock
Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
Gianfranco
G
Delle Fave
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy.
Ada
A
Piepoli
Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
Maurizio
M
Cantore
Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.
Wei
W
Zheng
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Brian M
BM
Wolpin
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Laufey T
LT
Amundadottir
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Federico
F
Canzian
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
C509186:TERT protein, human; D019098:Telomerase
pancreatic cancer; polymorphisms; susceptibility; telomerase