Fulltext

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Campa D 1 , Matarazzi M 1 , Greenhalf W 2 , Bijlsma M 3 , Saum KU 4 , Pasquali C 5 Show all authors , van Laarhoven H 3 , Szentesi A 6 , Federici F 7 , Vodicka P 8 , Funel N 9 , Pezzilli R 10 , Bueno-de-Mesquita HB 11 , Vodickova L 8 , Basso D 12 , Obazee O 13 , Hackert T 14 , Soucek P 15 , Cuk K 4 , Kaiser J 14 , Sperti C 16 , Lovecek M 17 , Capurso G 18 , Mohelnikova-Duchonova B 19 , Khaw KT 20 , König AK 14 , Kupcinskas J 21 , Kaaks R 22 , Bambi F 23 , Archibugi L 18 , Mambrini A 7 , Cavestro GM 24 , Landi S 1 , Hegyi P 6 , Izbicki JR 25 , Gioffreda D 26 , Zambon CF 16 , Tavano F 26 , Talar-Wojnarowska R 27 , Jamroziak K 28 , Key TJ 29 , Fave GD 18 , Strobel O 14 , Jonaitis L 21 , Andriulli A 26 , Lawlor RT 30 , Pirozzi F 31 , Katzke V 22 , Valsuani C 7 , Vashist YK 25 , Brenner H 4 , Canzian F 13

Affiliations 

  • 1 Department of Biology, University of Pisa, Pisa, Italy
  • 2 Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom
  • 3 Medical Oncology, Academic Medical Centre, Amsterdam, The Netherlands
  • 4 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 5 Pancreatic and Digestive Endocrine Surgery - Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
  • 6 Institute for Translational Medicine, University of Pécs, Pécs, Hungary
  • 7 Oncological Department, Azienda USL Toscana Nord Ovest, Oncological Unit of Massa Carrara, Carrara, Italy
  • 8 Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic
  • 9 Department of Surgery, Unit of Experimental Surgical Pathology, University of Pisa, Pisa, Italy
  • 10 Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital, Bologna, Italy
  • 11 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 12 Department of Laboratory Medicine, University-Hospital of Padova, Padua, Italy
  • 13 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 14 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
  • 15 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  • 16 Third Surgical Clinic - Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
  • 17 Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
  • 18 Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University, Rome, Italy
  • 19 Department of Oncology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
  • 20 University of Cambridge School of Clinical Medicine Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, United Kingdom
  • 21 Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
  • 22 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 23 Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy
  • 24 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy
  • 25 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 26 Division of Gastroenterology and Molecular Biology Lab, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
  • 27 Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
  • 28 Institute of Hematology and Transfusion Medicine, Warsaw, Poland
  • 29 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 30 ARC-NET, University and Hospital Trust of Verona, Verona, Italy
  • 31 Division of Abdominal Surgery, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
Int J Cancer, 2019 03 15;144(6):1275-1283.
PMID: 30325019 DOI: 10.1002/ijc.31928

Abstract

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications