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

  • Mitchell J. Machiela
  • , Jonathan N. Hofmann
  • , Robert Carreras-Torres
  • , Kevin M. Brown
  • , Mattias Johansson
  • , Zhaoming Wang
  • , Matthieu Foll
  • , Peng Li
  • , Nathaniel Rothman
  • , Sharon A. Savage
  • , Valerie Gaborieau
  • , James D. McKay
  • , Yuanqing Ye
  • , Marc Henrion
  • , Fiona Bruinsma
  • , Susan Jordan
  • , Gianluca Severi
  • , Kristian Hveem
  • , Lars J. Vatten
  • , Tony Fletcher
    • Kvetoslava Koppova, Susanna C. Larsson, Alicja Wolk, Rosamonde E. Banks, Peter J. Selby, Douglas F. Easton, Paul Pharoah, Gabriella Andreotti, Laura E.Beane Freeman, Stella Koutros, Demetrius Albanes, Satu Mannisto, Stephanie Weinstein, Peter E. Clark, Todd E. Edwards, Loren Lipworth, Susan M. Gapstur, Victoria L. Stevens, Hallie Carol, Matthew L. Freedman, Mark M. Pomerantz, Eunyoung Cho, Peter Kraft, Mark A. Preston, Kathryn M. Wilson, J. Michael Gaziano, Howard S. Sesso, Amanda Black, Neal D. Freedman, Wen Yi Huang, John G. Anema, Richard J. Kahnoski, Brian R. Lane, Sabrina L. Noyes, David Petillo, Leandro M. Colli, Joshua N. Sampson, Celine Besse, Helene Blanche, Anne Boland, Laurie Burdette, Egor Prokhortchouk, Konstantin G. Skryabin, Meredith Yeager, Mirjana Mijuskovic, Miodrag Ognjanovic, Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Neonila Szeszenia-Dabrowska, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, H. Bas Bueno-de-Mesquita, Federico Canzian, Eric J. Duell, Börje Ljungberg, Raviprakash T. Sitaram, Ulrike Peters, Emily White, Garnet L. Anderson, Lisa Johnson, Juhua Luo, Julie Buring, I. Min Lee, Wong Ho Chow, Lee E. Moore, Christopher Wood, Timothy Eisen, James Larkin, Toni K. Choueiri, G. Mark Lathrop, Bin Tean Teh, Jean Francois Deleuze, Xifeng Wu, Richard S. Houlston, Paul Brennan, Stephen J. Chanock, Ghislaine Scelo, Mark P. Purdue
  • National Institutes of Health
  • International Agency for Research on Cancer
  • St. Jude Children Research Hospital
  • University of Texas MD Anderson Cancer Center
  • Icahn School of Medicine at Mount Sinai
  • Cancer Council Victoria
  • Queensland Institute of Medical Research
  • University of Queensland
  • University of Melbourne
  • Human Genetics Foundation (HuGeF)
  • University of Southern Queensland
  • Norwegian University of Science and Technology
  • London School of Hygiene and Tropical Medicine
  • Regional Authority of Public Health in Banska Bystrica
  • Karolinska Institutet
  • University of Leeds
  • University of Cambridge
  • National Institute for Health and Welfare
  • Vanderbilt University
  • American Cancer Society
  • Dana-Farber Cancer Institute
  • Brown University
  • Harvard University
  • Brigham and Women’s Hospital
  • Veterans Administration
  • Spectrum Health
  • Michigan State University
  • Van Andel Institute
  • Evry
  • Centre d'Etude du Polymorphisme Humain (CEPH)
  • Russian Academy of Sciences
  • Kurchatov Scientific Center
  • Military Medical Academy
  • International Organization for Cancer Prevention and Research
  • Masaryk Memorial Cancer Institute
  • Charles University
  • Palacký University Olomouc
  • National Institute of Public Health
  • Russian Academy of Medical Sciences - N.N. Blokhin Russian Cancer Research Center
  • Carol Davila University of Medicine and Pharmacy
  • Maria Sklodowska-Curie Institute of Oncology
  • Pomeranian Medical University in Szczecin
  • National Directorate of Environmental Health
  • Nofer Institute of Occupational Medicine
  • Institut national de la santé et de la recherche médicale
  • Gustave Roussy Cancer Campus
  • CeRePP
  • Sorbonne Université
  • Paris-Hôpital Tenon
  • National Institute of Public Health and the Environment
  • Utrecht University
  • Imperial College London
  • University of Malaya
  • German Cancer Research Center
  • Institute Catala Oncologia
  • Umeå University
  • Fred Hutchinson Cancer Research Center
  • Indiana University Bloomington
  • Royal Marsden NHS Foundation Trust
  • McGill University
  • Institute of Cancer Research

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

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. This large Mendelian randomization study utilizes a risk score of telomere length associated genetic variants to demonstrate a strong association between longer predicted leukocyte telomere length and increased risk of developing common subtypes of renal cell carcinoma.
Original languageEnglish
Pages (from-to)747-754
Number of pages8
JournalEuropean Urology
Volume72
Issue number5
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

Keywords

  • Genetic variants
  • Mendelian randomization
  • Renal cell carcinoma
  • Risk
  • Telomere length

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  • 46 Citations
  • 1 Other contribution

  • Corrigendum re “Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma”

    Machiela, M. J., Hofmann, J. N., Carreras-Torres, R., Brown, K. M., Johansson, M., Wang, Z., Foll, M., Li, P., Rothman, N., Savage, S. A., Gaborieau, V., McKay, J. D., Ye, Y., Henrion, M., Bruinsma, F., Jordan, S., Severi, G., Hveem, K., Vatten, L. J. & Fletcher, T. & 92 others, Koppova, K., Larsson, S. C., Wolk, A., Banks, R. E., Selby, P. J., Easton, D. F., Pharoah, P., Andreotti, G., Freeman, L. E. B., Koutros, S., Albanes, D., Mannisto, S., Weinstein, S., Clark, P. E., Edwards, T. E., Lipworth, L., Gapstur, S. M., Stevens, V. L., Carol, H., Freedman, M. L., Pomerantz, M. M., Cho, E., Kraft, P., Preston, M. A., Wilson, K. M., Gaziano, J. M., Sesso, H. S., Black, A., Freedman, N. D., Huang, W. Y., Anema, J. G., Kahnoski, R. J., Lane, B. R., Noyes, S. L., Petillo, D., Colli, L. M., Sampson, J. N., Besse, C., Blanche, H., Boland, A., Burdette, L., Prokhortchouk, E., Skryabin, K. G., Yeager, M., Mijuskovic, M., Ognjanovic, M., Foretova, L., Holcatova, I., Janout, V., Mates, D., Mukeriya, A., Rascu, S., Zaridze, D., Bencko, V., Cybulski, C., Fabianova, E., Jinga, V., Lissowska, J., Lubinski, J., Navratilova, M., Rudnai, P., Szeszenia-Dabrowska, N., Benhamou, S., Cancel-Tassin, G., Cussenot, O., Bueno-de-Mesquita, H. B., Canzian, F., Duell, E. J., Ljungberg, B., Sitaram, R. T., Peters, U., White, E., Anderson, G. L., Johnson, L., Luo, J., Buring, J., Lee, I. M., Chow, W. H., Moore, L. E., Wood, C., Eisen, T., Larkin, J., Choueiri, T. K., Lathrop, G. M., Teh, B. T., Deleuze, J. F., Wu, X., Houlston, R. S., Brennan, P., Chanock, S. J., Scelo, G. & Purdue, M. P., 1 Sept 2018

    Research output: Other contribution

    Open Access
    1 Citation (Scopus)

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