EURURO Vol. 72 No. 5

Torino, Italy;

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

HUNT

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

Department of

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

London School of Hygiene

and Tropical Medicine, University of London, London, UK;

Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia;

Institute of

Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;

Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building,

St James

’

s University Hospital, Leeds, UK;

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

UK;

National Institute for Health and Welfare, Helsinki, Finland;

Vanderbilt-Ingram Cancer Center, Nashville, TN, USA;

American Cancer Society, Atlanta,

GA, USA;

Dana-Farber Cancer Institute, Boston, MA, USA;

Brown University, Providence, RI, USA;

Harvard T.H. Chan School of Public Health, Boston, MA,

USA;

Brigham and Women

’

s Hospital, Boston, MA, USA;

Veterans Administration, Boston, MA, USA;

Division of Urology, Spectrum Health, Grand Rapids,

MI, USA;

College of Human Medicine, Michigan State University, Grand Rapids, MI, USA;

Van Andel Research Institute, Center for Cancer Genomics and

Quantitative Biology, Grand Rapids, MI, USA;

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;

Center

‘

Bioengineering

’

of the Russian Academy of Sciences, Moscow, Russian Federation;

Kurchatov Scientific Center, Moscow, Russian

Federation;

Clinic for Nephrology, Military Medical Academy, Belgrade, Serbia;

International Organization for Cancer Prevention and Research (IOCPR),

Belgrade, Serbia;

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

Second Faculty of

Medicine, Institute of Public Health and Preventive Medicine, Charles University, Prague, Czech Republic;

Department of Preventive Medicine, Faculty of

Medicine, Palacky University, Czech Republic;

National Institute of Public Health, Bucharest, Romania;

Russian N.N. Blokhin Cancer Research Centre,

Moscow, Russian Federation;

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

First Faculty of Medicine,

Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic;

International Hereditary Cancer Center, Department of Genetics and

Pathology, Pomeranian Medical University, Szczecin, Poland;

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

National

Public Health Center, National Directorate of Environmental Health, Budapest, Hungary;

Department of Epidemiology, Institute of Occupational Medicine,

Lodz, Poland;

INSERM U946, Paris, France;

CNRS UMR8200, Institute Gustave Roussy, Villejuif, 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;

Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands;

aaa

Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands;

bbb

Department of Epidemiology and Biostatistics,

The School of Public Health, Imperial College London, St Mary

’

s Campus, Norfolk Place, London, UK;

ccc

Department of Social & Preventive Medicine, Faculty of

Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia;

ddd

Genomic Epidemiology Group, German Cancer Research Center (DKFZ),

Heidelberg, Germany;

eee

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona,

Spain;

fff

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

ggg

Fred Hutchinson Cancer Research

Center, Seattle, WA, USA;

hhh

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

iii

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

jjj

University of Cambridge, Cambridge, UK;

kkk

Royal

Marsden NHS Foundation Trust, London, UK;

lll

McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada;

mmm

The Institute of Cancer

Research, London, UK

Article info

Article history:

Accepted July 17, 2017

Associate Editor:

Giacomo Novara

Keywords:

Renal cell carcinoma

Telomere length

Genetic variants

Mendelian randomization

Risk

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 fromnine 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% con

dence interval [CI]:

= 1.70

–

2.53,

0.0001). As a sensitivity analysis, we excluded two telomere length variants in

linkage disequilibrium (R

0.5) with GWAS-identi

ed RCC risk variants (rs10936599 and

rs9420907) from the telomere length GRS; despite this exclusion, a statistically signi

cant

association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36

–

2.21,

0.0001).

Exploratory analyses for individual histologic subtypes suggested comparable associations with

the telomere length GRS for clear cell (

= 5573, OR = 1.93, 95% CI = 1.50

–

2.49,

0.0001),

papillary (

= 573, OR = 1.96, 95% CI = 1.01

–

3.81,

= 0.046), and chromophobe RCC (

= 203,

OR = 2.37, 95% CI = 0.78

–

7.17,

= 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.

Published by Elsevier B.V. on behalf of European Association of Urology.

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