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.

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

2nd Faculty of Medicine Institute of Public Health and Preventive Medicine Charles University Prague Czech Republic

American Cancer Society Atlanta GA USA

Brigham and Women's Hospital Boston MA USA

Brigham and Women's Hospital Boston MA USA; Veterans Administration Boston MA USA

Brown University Providence RI USA

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Australia

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 Torino Italy; Centre de Recherche en Épidémiologie et Santé des Populations Université Paris Saclay UPS USQ Gustave Roussy Villejuif France

Carol Davila University of Medicine and Pharmacy Th Burghele Hospital Bucharest Romania

Center 'Bioengineering' of the Russian Academy of Sciences Moscow Russian Federation; Kurchatov Scientific Center Moscow Russian Federation

Centre National de Recherche en Genomique Humaine Institut de biologie François Jacob Commissariat à l'Energie Atomique et aux Energies Alternatives Evry France

Centre National de Recherche en Genomique Humaine 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

CeRePP Paris France; UPMC Univ Paris 06 Institut Universitaire de Cancérologie Paris France

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

Clinic for Nephrology Military Medical Academy Belgrade Serbia

Dana Farber Cancer Institute Boston MA USA

Department for Determinants of Chronic Diseases 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 and Preventive Medicine Faculty of Medicine University of Malaya Pantai Valley Kuala Lumpur Malaysia

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Epidemiology and Biostatistics School of Public Health Indiana University Bloomington Bloomington IN USA

Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Epidemiology Institute of Occupational Medicine Lodz Poland

Department of Oncology and Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Preventive Medicine Faculty of Medicine Palacky University Czech Republic

Department of Public Health and General Practice Faculty of Medicine Norwegian University of Science and Technology Trondheim Norway

Department of Surgical and Perioperative Sciences Urology and Andrology Umeå University Umeå Sweden

Department of Urology The University of Texas MD Anderson Cancer Center Houston TX USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department Health and Human Services Bethesda MS USA

Division of Urology Spectrum Health Grand Rapids MI USA

Division of Urology Spectrum Health Grand Rapids MI USA; College of Human Medicine Michigan State University Grand Rapids MI USA

Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain Paris France

Fred Hutchinson Cancer Research Center Seattle WA USA

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Harvard T H Chan School of Public Health Boston MA USA

Harvard T H Chan School of Public Health Boston MA USA; Brigham and Women's Hospital Boston MA USA

HUNT Research Centre Department of Public Health and General Practice Norwegian University of Science and Technology Levanger Sweden

Icahn School of Medicine New York NY USA

INSERM U946 Paris France; CNRS UMR8200 Institute Gustave Roussy Villejuif France

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

International Agency for Research on Cancer Lyon France

International Hereditary Cancer Center Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

International Organization for Cancer Prevention and Research Belgrade Serbia

Leeds Institute of Cancer and Pathology University of Leeds Cancer Research Building St James's University Hospital Leeds UK

London School of Hygiene and Tropical Medicine University of London London UK

McGill University and Genome Quebec Innovation Centre Montreal QC Canada

National Institute for Health and Welfare Helsinki Finland

National Institute of Public Health Bucharest Romania

National Public Health Center National Directorate of Environmental Health Budapest Hungary

QIMR Berghofer Medical Research Institute Herston Queensland Australia; School of Public Health The University of Queensland Brisbane Australia

Regional Authority of Public Health in Banska Bystrica Banska Bystrica Slovakia

Royal Marsden NHS Foundation Trust London UK

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

St Jude Children's Research Hospital Memphis TN USA

The Institute of Cancer Research London UK

The M Sklodowska Curie Cancer Center and Institute of Oncology Warsaw Poland

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Barcelona Spain

University of Cambridge Cambridge UK

Van Andel Research Institute Center for Cancer Genomics and Quantitative Biology Grand Rapids MI USA

Vanderbilt Ingram Cancer Center Nashville TN USA

Comment In

Eur Urol. 2017 Nov;72(5):755-756. doi: 10.1016/j.eururo.2017.08.008. PubMed

Erratum In

Eur Urol. 2018 Sep;74(3):e85-e86. doi: 10.1016/j.eururo.2018.05.017. PubMed

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