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.

1st Department of Propaedeutic Surgery School of Medicine University of Athens Athens Greece

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford United Kingdom

Department of Basic Medical Science Laboratory of Biology School of Medicine University of Athens Athens Greece

Department of Biology University of Pisa Pisa Italy

Department of Determinants of Chronic Diseases Bilthoven The Netherlands

Department of Digestive Tract Diseases Medical University of Łodz Łodz Poland

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco CA

Department of Epidemiology and Public Health Yale School of Public Health New Haven CT

Department of Epidemiology Harvard School of Public Health Boston MA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD

Department of Epidemiology University of Washington Seattle WA

Department of Gastroenterology and Hepatology University Medical Centre Utrecht The Netherlands

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of Gastrointestinal Medical Oncology University of Texas M D Anderson Cancer Center Houston TX

Department of General Surgery University Hospital Heidelberg Heidelberg Germany

Department of Health Sciences Research Mayo Clinic College of Medicine Rochester MN

Department of Hematology Institute of Hematology and Transfusion Medicine Warsaw Poland

Department of Laboratory Medicine University Hospital of Padua Padua Italy

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Medicine and Vanderbilt Ingram Cancer Center Vanderbilt University Medical Center Nashville TN

Department of Medicine DIMED University of Padua Padua Italy

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Science of Czech Republic Prague Czech Republic

Department of Oncology Palacky University Medical School and Teaching Hospital in Olomouc Olomouc Czech Republic

Department of Oncology The Johns Hopkins University School of Medicine Baltimore MD

Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Surgery 2nd Faculty of Medicine Charles University Prague and Central Military Hospital Prague Czech Republic

Department of Surgery Gastroenterology and Oncology University of Padua Padua Italy

Department of Surgery Unit of Experimental Surgical Pathology University Hospital of Pisa Pisa Italy

Department of Surgery University Health Network University of Toronto Toronto ON Canada

Department of Toxicogenomics National Institute of Public Health Prague Czech Republic

Digestive and Liver Disease Unit S Andrea Hospital 'Sapienza' University of Rome Rome Italy

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology Departments of Obstetrics and Gynecology Environmental Medicine and Population Health New York University School of Medicine New York NY

Division of Gastroenterology and Research Laboratory IRCCS Scientific Institute and Regional General Hospital Casa Sollievo Della Sofferenza San Giovanni Rotondo Italy

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA

Divisions of Preventive Medicine and Aging Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA

Epidemiology Research Program American Cancer Society Atlanta GA

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

MRC Epidemiology Unit Institute of Metabolic Science University of Cambridge Cambridge United Kingdom

National Institute for Health Research Liverpool Pancreas Biomedical Research Unit University of Liverpool Liverpool United Kingdom

Oncology Department ASL1 Massa Carrara Massa Carrara Italy

Pancreas Unit Department of Digestive Diseases and Internal Medicine Sant'Orsola Malpighi Hospital Bologna Italy

Surgical and Oncological Department Pancreas Institute University and Hospital Trust of Verona Verona Italy

Surgical Clinic 4 University of Padua Padua Italy

Zobrazit více v PubMed

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014;64:9–29. PubMed

Fesinmeyer MD, Austin MA, Li CI, De Roos AJ, Bowen DJ. Differences in survival by histologic type of pancreatic cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005;14:1766–1773. PubMed

Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology. 2008;134:95–101. PubMed PMC

Hidalgo M. Pancreatic cancer. The New England journal of medicine. 2010;362:1605–1617. PubMed

Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA: a cancer journal for clinicians. 2013;63:318–348. PubMed PMC

Aird I, Lee DR, Roberts JA. ABO blood groups and cancer of oesophagus, cancerof pancreas, and pituitary adenoma. Br Med J. 1960;1:1163–1166. PubMed PMC

Risch HA, Lu L, Wang J, Zhang W, Ni Q, Gao YT, Yu H. ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis. American journal of epidemiology. 2013;177:1326–1337. PubMed PMC

Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS, Petersen GM, Arslan AA, Bueno-de-Mesquita HB, Gross M, Helzlsouer K, Jacobs EJ, LaCroix A, Zheng W, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41:986–990. PubMed PMC

Low SK, Kuchiba A, Zembutsu H, Saito A, Takahashi A, Kubo M, Daigo Y, Kamatani N, Chiku S, Totsuka H, Ohnami S, Hirose H, et al. Genome-wide association study of pancreatic cancer in Japanese population. PloS one. 2010;5:e11824. PubMed PMC

Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M, Helzlsouer K, Holly EA, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42:224–228. PubMed PMC

Wu C, Miao X, Huang L, Che X, Jiang G, Yu D, Yang X, Cao G, Hu Z, Zhou Y, Zuo C, Wang C, et al. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet. 2011;44:62–66. PubMed

Rizzato C, Campa D, Giese N, Werner J, Rachakonda PS, Kumar R, Schanne M, Greenhalf W, Costello E, Khaw KT, Key TJ, Siddiq A, et al. Pancreatic cancer susceptibility loci and their role in survival. PloS one. 2011;6:e27921. PubMed PMC

Wolpin BM, Rizzato C, Kraft P, Kooperberg C, Petersen GM, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Canzian F, Duell EJ, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014;46:994–1000. PubMed PMC

Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106:661–673. PubMed

Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. The Journal of clinical investigation. 2013;123:996–1002. PubMed PMC

de Lange T. How telomeres solve the end-protection problem. Science. 2009;326:948–952. PubMed PMC

Martinez P, Blasco MA. Role of shelterin in cancer and aging. Aging Cell. 2010;9:653–666. PubMed

McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annual review of genetics. 2000;34:331–358. PubMed

McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet. 2008;40:1404–1406. PubMed PMC

Mocellin S, Verdi D, Pooley KA, Landi MT, Egan KM, Baird DM, Prescott J, De Vivo I, Nitti D. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis. Journal of the National Cancer Institute. 2012;104:840–854. PubMed PMC

Rajaraman P, Melin BS, Wang Z, McKean-Cowdin R, Michaud DS, Wang SS, Bondy M, Houlston R, Jenkins RB, Wrensch M, Yeager M, Ahlbom A, et al. Genome-wide association study of glioma and meta-analysis. Human genetics. 2012;131:1877–1888. PubMed PMC

Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, Ricketts M, Linger R, Nsengimana J, Deloukas P, Huddart RA, Bishop DT, et al. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010;42:604–607. PubMed PMC

Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, Real FX, Van Den Berg D, Matullo G, Baris D, Thun M, Kiemeney LA, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42:978–984. PubMed PMC

Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen WV, Spitz MR, Eisen T, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet. 2008;40:1407–1409. PubMed PMC

Haiman CA, Chen GK, Vachon CM, Canzian F, Dunning A, Millikan RC, Wang X, Ademuyiwa F, Ahmed S, Ambrosone CB, Baglietto L, Balleine R, et al. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet. 2011;43:1210–1214. PubMed PMC

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013;45:371–384. 84e1–84e2. PubMed PMC

Kote-Jarai Z, Olama AA, Giles GG, Severi G, Schleutker J, Weischer M, Campa D, Riboli E, Key T, Gronberg H, Hunter DJ, Kraft P, et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet. 2011;43:785–791. PubMed PMC

Kote-Jarai Z, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, Dadaev T, Jugurnauth-Little S, Ross-Adams H, Al Olama AA, Benlloch S, Halim S, Russel R, Dunning AM, et al. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Human molecular genetics. 2013;22:2520–2528. PubMed PMC

Chubb D, Weinhold N, Broderick P, Chen B, Johnson DC, Forsti A, Vijayakrishnan J, Migliorini G, Dobbins SE, Holroyd A, Hose D, Walker BA, et al. Common variation at 3q26.2-6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet. 2013;45:1221–1225. PubMed PMC

Jones AM, Beggs AD, Carvajal-Carmona L, Farrington S, Tenesa A, Walker M, Howarth K, Ballereau S, Hodgson SV, Zauber A, Bertagnolli M, Midgley R, et al. TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut. 2012;61:248–254. PubMed PMC

Campa D, Rizzato C, Capurso G, Giese N, Funel N, Greenhalf W, Soucek P, Gazouli M, Pezzilli R, Pasquali C, Talar-Wojnarowska R, Cantore M, et al. Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium. Dig Liver Dis. 2012 PubMed

Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–989. PubMed PMC

Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45:422–427. 7e1–7e2. PubMed PMC

Prescott J, Kraft P, Chasman DI, Savage SA, Mirabello L, Berndt SI, Weissfeld JL, Han J, Hayes RB, Chanock SJ, Hunter DJ, De Vivo I. Genome-wide association study of relative telomere length. PloS one. 2011;6:e19635. PubMed PMC

Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–913. PubMed

Gao X, Starmer J, Martin ER. A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genetic epidemiology. 2008;32:361–369. PubMed

Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, Cherry JM, Snyder M. Annotation of functional variation in personal genomes using RegulomeDB. Genome research. 2012;22:1790–1797. PubMed PMC

Cechova H, Lassuthova P, Novakova L, Belickova M, Stemberkova R, Jencik J, Stankova M, Hrabakova P, Pegova K, Zizkova H, Cermak J. Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia. Neoplasma. 2012;59:168–174. PubMed

Grundberg E, Small KS, Hedman AK, Nica AC, Buil A, Keildson S, Bell JT, Yang TP, Meduri E, Barrett A, Nisbett J, Sekowska M, et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet. 2012;44:1084–1089. PubMed PMC

Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics (Oxford, England) 2008;24:2938–2939. PubMed PMC

Beesley J, Pickett HA, Johnatty SE, Dunning AM, Chen X, Li J, Michailidou K, Lu Y, Rider DN, Palmieri RT, Stutz MD, Lambrechts D, et al. Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers. PloS one. 2011;6:e24987. PubMed PMC

Stacey SN, Sulem P, Masson G, Gudjonsson SA, Thorleifsson G, Jakobsdottir M, Sigurdsson A, Gudbjartsson DF, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, et al. New common variants affecting susceptibility to basal cell carcinoma. Nat Genet. 2009;41:909–914. PubMed PMC

Zhao Y, Chen G, Song X, Chen H, Mao Y, Lu D. Fine-mapping of a region of chromosome 5p15.33 (TERT-CLPTM1L) suggests a novel locus in TERT and a CLPTM1L haplotype are associated with glioma susceptibility in a Chinese population. International journal of cancer Journal international du cancer. 2012;131:1569–1576. PubMed

Shiraishi K, Kunitoh H, Daigo Y, Takahashi A, Goto K, Sakamoto H, Ohnami S, Shimada Y, Ashikawa K, Saito A, Watanabe S, Tsuta K, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet. 2012;44:900–903. PubMed

A user's guide to the encyclopedia of DNA elements (ENCODE) PLoS biology. 2011;9:e1001046. PubMed PMC

Melin BS, Nordfjall K, Andersson U, Roos G. hTERT cancer risk genotypes are associated with telomere length. Genetic epidemiology. 2012;36:368–372. PubMed

Campa D, Mergarten B, De Vivo I, Boutron-Ruault MC, Racine A, Severi G, Nieters A, Katzke VA, Trichopoulou A, Yiannakouris N, Trichopoulos D, Boeing H, et al. Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2014 PubMed

Lynch SM, Major JM, Cawthon R, Weinstein SJ, Virtamo J, Lan Q, Rothman N, Albanes D, Stolzenberg-Solomon RZ. A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study. International journal of cancer Journal international du cancer. 2013;133:2672–2680. PubMed PMC

Skinner HG, Gangnon RE, Litzelman K, Johnson RA, Chari ST, Petersen GM, Boardman LA. Telomere length and pancreatic cancer: a case-control study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2012;21:2095–2100. PubMed PMC

Chung CC, Chanock SJ. Current status of genome-wide association studies in cancer. Human genetics. 2011 PubMed

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Genetic Susceptibility in Understanding of Pancreatic Ductal Adenocarcinoma Risk: A Decade-Long Effort of the PANDORA Consortium

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

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

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk