Fulltext

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Machiela MJ 1 , Hofmann JN 1 , Carreras-Torres R 2 , Brown KM 1 , Johansson M 2 , Wang Z 3 Show all authors , Foll M 2 , Li P 2 , Rothman N 1 , Savage SA 1 , Gaborieau V 2 , McKay JD 2 , Ye Y 4 , Henrion M 5 , Bruinsma F 6 , Jordan S 7 , Severi G 8 , Hveem K 9 , Vatten LJ 10 , Fletcher T 11 , Koppova K 12 , Larsson SC 13 , Wolk A 13 , Banks RE 14 , Selby PJ 14 , Easton DF 15 , Pharoah P 15 , Andreotti G 1 , Freeman LEB 1 , Koutros S 1 , Albanes D 1 , Mannisto S 16 , Weinstein S 1 , Clark PE 17 , Edwards TE 17 , Lipworth L 17 , Gapstur SM 18 , Stevens VL 18 , Carol H 19 , Freedman ML 19 , Pomerantz MM 19 , Cho E 20 , Kraft P 21 , Preston MA 22 , Wilson KM 21 , Gaziano JM 23 , Sesso HS 21 , Black A 1 , Freedman ND 1 , Huang WY 1 , Anema JG 24 , Kahnoski RJ 24 , Lane BR 25 , Noyes SL 26 , Petillo D 26 , Colli LM 1 , Sampson JN 1 , Besse C 27 , Blanche H 28 , Boland A 27 , Burdette L 1 , Prokhortchouk E 29 , Skryabin KG 29 , Yeager M 1 , Mijuskovic M 30 , Ognjanovic M 31 , Foretova L 31 , Holcatova I 32 , Janout V 33 , Mates D 34 , Mukeriya A 35 , Rascu S 36 , Zaridze D 35 , Bencko V 37 , Cybulski C 38 , Fabianova E 12 , Jinga V 37 , Lissowska J 39 , Lubinski J 40 , Navratilova M 32 , Rudnai P 41 , Szeszenia-Dabrowska N 42 , Benhamou S 43 , Cancel-Tassin G 44 , Cussenot O 45 , Bueno-de-Mesquita HB 46 , Canzian F 47 , Duell EJ 48 , Ljungberg B 49 , Sitaram RT 49 , Peters U 50 , White E 50 , Anderson GL 50 , Johnson L 50 , Luo J 51 , Buring J 21 , Lee IM 52 , Chow WH 4 , Moore LE 1 , Wood C 53 , Eisen T 54 , Larkin J 55 , Choueiri TK 19 , Lathrop GM 56 , Teh BT 26 , Deleuze JF 57 , Wu X 4 , Houlston RS 58 , Brennan P 2 , Chanock SJ 1 , Scelo G 2 , Purdue MP 59

Affiliations 

  • 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA
  • 2 International Agency for Research on Cancer (IARC), Lyon, France
  • 3 St. Jude Children's Research Hospital, Memphis, TN, USA
  • 4 Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 5 Icahn School of Medicine, New York, NY, USA
  • 6 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia
  • 7 QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Public Health, The University of Queensland, Brisbane, Australia
  • 8 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia; Human Genetics Foundation (HuGeF), Torino, Italy; Centre de Recherche en Épidémiologie et Santé des Populations, Université Paris-Saclay, UPS, USQ, Gustave Roussy, Villejuif, France
  • 9 HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Sweden
  • 10 Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
  • 11 London School of Hygiene and Tropical Medicine, University of London, London, UK
  • 12 Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia
  • 13 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 14 Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, UK
  • 15 Department of Oncology, and Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 16 National Institute for Health and Welfare, Helsinki, Finland
  • 17 Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
  • 18 American Cancer Society, Atlanta, GA, USA
  • 19 Dana-Farber Cancer Institute, Boston, MA, USA
  • 20 Brown University, Providence, RI, USA
  • 21 Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 22 Brigham and Women's Hospital, Boston, MA, USA
  • 23 Brigham and Women's Hospital, Boston, MA, USA; Veterans Administration, Boston, MA, USA
  • 24 Division of Urology, Spectrum Health, Grand Rapids, MI, USA
  • 25 Division of Urology, Spectrum Health, Grand Rapids, MI, USA; College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
  • 26 Van Andel Research Institute, Center for Cancer Genomics and Quantitative Biology, Grand Rapids, MI, USA
  • 27 Centre National de Recherche en Genomique Humaine (CNRGH), Institut de biologie François Jacob, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France
  • 28 Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France
  • 29 Center 'Bioengineering' of the Russian Academy of Sciences, Moscow, Russian Federation; Kurchatov Scientific Center, Moscow, Russian Federation
  • 30 Clinic for Nephrology, Military Medical Academy, Belgrade, Serbia
  • 31 International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia
  • 32 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  • 33 Second Faculty of Medicine, Institute of Public Health and Preventive Medicine, Charles University, Prague, Czech Republic
  • 34 Department of Preventive Medicine, Faculty of Medicine, Palacky University, Czech Republic
  • 35 National Institute of Public Health, Bucharest, Romania
  • 36 Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation
  • 37 Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, Bucharest, Romania
  • 38 First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic
  • 39 The M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
  • 40 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 41 National Public Health Center, National Directorate of Environmental Health, Budapest, Hungary
  • 42 Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland
  • 43 INSERM U946, Paris, France; CNRS UMR8200, Institute Gustave Roussy, Villejuif, France
  • 44 CeRePP, Paris, France; UPMC Univ Paris 06, Institut Universitaire de Cancérologie, Paris, France
  • 45 CeRePP, Paris, France; UPMC Univ Paris 06, Institut Universitaire de Cancérologie, Paris, France; AP-HP, Department of Urology, Hopitaux Universitaires Est Parisien Tenon, Paris, France
  • 46 Department for 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, The School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, UK; Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia
  • 47 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 48 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
  • 49 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden
  • 50 Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 51 Department of Epidemiology and Biostatistics, School of Public Health Indiana University Bloomington, Bloomington, IN, USA
  • 52 Harvard T.H. Chan School of Public Health, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
  • 53 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 54 University of Cambridge, Cambridge, UK
  • 55 Royal Marsden NHS Foundation Trust, London, UK
  • 56 McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada
  • 57 Centre National de Recherche en Genomique Humaine (CNRGH), Institut de biologie François Jacob, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France; Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France
  • 58 The Institute of Cancer Research, London, UK
  • 59 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA. Electronic address: purduem@mail.nih.gov
Eur Urol, 2017 Nov;72(5):747-754.
PMID: 28797570 DOI: 10.1016/j.eururo.2017.07.015

Abstract

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).

CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

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

MeSH terms
Similar publications