TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Daniele Campa¹, Cosmeri Rizzato², Rachael Stolzenberg-Solomon³, Paola Pacetti⁴, Pavel Vodicka⁵, Sean P Cleary⁶, Gabriele Capurso⁷, H B As Bueno-de-Mesquita^{8

9

10

11}, Jens Werner¹², Maria Gazouli¹³, Katja Butterbach¹⁴, Audrius Ivanauskas¹⁵, Nathalia Giese¹², Gloria M Petersen¹⁶, Paola Fogar¹⁷, Zhaoming Wang³, Claudio Bassi¹⁸, Miroslav Ryska¹⁹, George E Theodoropoulos²⁰, Charles Kooperberg²¹, Donghui Li²², William Greenhalf²³, Claudio Pasquali²⁴, Thilo Hackert¹², Charles S Fuchs²⁵, Beatrice Mohelnikova-Duchonova²⁶, Cosimo Sperti²⁴, Niccola Funel²⁷, Aida Karina Dieffenbach^{14

28}, Nicholas J Wareham²⁹, Julie Buring³⁰, Ivana Holcátová³¹, Eithne Costello²³, Carlo-Federico Zambon³², Juozas Kupcinskas¹⁵, Harvey A Risch³³, Peter Kraft³⁴, Paige M Bracci³⁵, Raffaele Pezzilli³⁶, Sara H Olson³⁷, Howard D Sesso^{30

34}, Patricia Hartge³, Oliver Strobel¹², Ewa Małecka-Panas³⁸, Kala Visvanathan³⁹, Alan A Arslan⁴⁰, Sergio Pedrazzoli⁴¹, Pavel Souček⁴², Domenica Gioffreda⁴³, Timothy J Key⁴⁴, Renata Talar-Wojnarowska³⁸, Aldo Scarpa⁴⁵, Andrea Mambrini⁴, Eric J Jacobs⁴⁶, Krzysztof Jamroziak⁴⁷, Alison Klein⁴⁸, Francesca Tavano⁴³, Franco Bambi⁴⁹, Stefano Landi⁵⁰, Melissa A Austin⁵¹, Ludmila Vodickova⁵, Hermann Brenner^{14

28}, Stephen J Chanock³, Gianfranco Delle Fave⁷, Ada Piepoli⁴³, Maurizio Cantore⁴, Wei Zheng⁵², Brian M Wolpin²⁵, Laufey T Amundadottir³, Federico Canzian²

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁴ Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
⁵ Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic.
⁶ Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁷ Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
⁸ Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
⁹ Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
¹⁰ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
¹¹ Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹² Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹⁶ Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN.
¹⁷ Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy.
¹⁸ Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy.
¹⁹ Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic.
²⁰ 1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece.
²¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
²² Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
²³ National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
²⁴ Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
²⁶ Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic.
²⁷ Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
²⁸ German Cancer Consortium (DKTK), Heidelberg, Germany.
²⁹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
³⁰ Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
³¹ Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
³² Department of Medicine - DIMED, University of Padua, Padua, Italy.
³³ Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT.
³⁴ Department of Epidemiology, Harvard School of Public Health, Boston, MA.
³⁵ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
³⁶ Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
³⁷ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁸ Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
³⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
⁴⁰ Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY.
⁴¹ Surgical Clinic 4, University of Padua, Padua, Italy.
⁴² Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.
⁴³ Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy.
⁴⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
⁴⁵ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
⁴⁶ Epidemiology Research Program, American Cancer Society, Atlanta, GA.
⁴⁷ Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
⁴⁸ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
⁴⁹ Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy.
⁵⁰ Department of Biology, University of Pisa, Pisa, Italy.
⁵¹ Department of Epidemiology, University of Washington, Seattle, WA.
⁵² Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.

PMID: 25940397
PMCID: PMC4548797
DOI: 10.1002/ijc.29590

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Daniele Campa et al. Int J Cancer. 2015.

. 2015 Nov 1;137(9):2175-83.

doi: 10.1002/ijc.29590. Epub 2015 Jun 19.

Authors

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁴ Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
⁵ Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic.
⁶ Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁷ Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
⁸ Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
⁹ Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
¹⁰ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
¹¹ Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹² Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
¹⁶ Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN.
¹⁷ Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy.
¹⁸ Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy.
¹⁹ Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic.
²⁰ 1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece.
²¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
²² Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
²³ National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
²⁴ Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
²⁶ Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic.
²⁷ Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
²⁸ German Cancer Consortium (DKTK), Heidelberg, Germany.
²⁹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
³⁰ Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
³¹ Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
³² Department of Medicine - DIMED, University of Padua, Padua, Italy.
³³ Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT.
³⁴ Department of Epidemiology, Harvard School of Public Health, Boston, MA.
³⁵ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
³⁶ Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
³⁷ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁸ Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
³⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
⁴⁰ Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY.
⁴¹ Surgical Clinic 4, University of Padua, Padua, Italy.
⁴² Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.
⁴³ Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy.
⁴⁴ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
⁴⁵ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
⁴⁶ Epidemiology Research Program, American Cancer Society, Atlanta, GA.
⁴⁷ Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
⁴⁸ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
⁴⁹ Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy.
⁵⁰ Department of Biology, University of Pisa, Pisa, Italy.
⁵¹ Department of Epidemiology, University of Washington, Seattle, WA.
⁵² Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.

PMID: 25940397
PMCID: PMC4548797
DOI: 10.1002/ijc.29590

Abstract

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.

Keywords: pancreatic cancer; polymorphisms; susceptibility; telomerase.

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Conflict of interest statement

None of the authors has conflicts of interests to declare.

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TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Affiliations

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Authors

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Abstract

Conflict of interest statement

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