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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma
MJ. Machiela, JN. Hofmann, R. Carreras-Torres, KM. Brown, M. Johansson, Z. Wang, M. Foll, P. Li, N. Rothman, SA. Savage, V. Gaborieau, JD. McKay, Y. Ye, M. Henrion, F. Bruinsma, S. Jordan, G. Severi, K. Hveem, LJ. Vatten, T. Fletcher, K. Koppova,...
Language English Country Switzerland
Document type Journal Article, Meta-Analysis, Multicenter Study, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
- MeSH
- Genome-Wide Association Study MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease MeSH
- Risk Assessment MeSH
- Telomere Homeostasis * MeSH
- Polymorphism, Single Nucleotide * MeSH
- Carcinoma, Renal Cell blood genetics pathology MeSH
- Leukocytes chemistry MeSH
- Humans MeSH
- Mendelian Randomization Analysis MeSH
- Kidney Neoplasms blood genetics pathology MeSH
- Odds Ratio MeSH
- Risk Factors MeSH
- Case-Control Studies MeSH
- Telomere genetics pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
American Cancer Society Atlanta GA USA
AP HP Department of Urology Hopitaux Universitaires Est Parisien Tenon Paris France
Brigham and Women's Hospital Boston MA USA
Brown University Providence RI USA
Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Australia
Carol Davila University of Medicine and Pharmacy Th Burghele Hospital Bucharest Romania
Center 'Bioengineering' of the Russian Academy of Sciences Moscow Russian Federation
Clinic for Nephrology Military Medical Academy Belgrade Serbia
CNRS UMR8200 Institute Gustave Roussy Villejuif France
College of Human Medicine Michigan State University Grand Rapids MI USA
Dana Farber Cancer Institute Boston MA USA
Department for Determinants of Chronic Diseases Bilthoven The Netherlands
Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic
Department of Epidemiology Institute of Occupational Medicine Lodz Poland
Department of Gastroenterology and Hepatology University Medical Centre Utrecht The Netherlands
Department of Preventive Medicine Faculty of Medicine Palacky University Czech Republic
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 Urology Spectrum Health 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
Human Genetics Foundation Torino Italy
Icahn School of Medicine New York NY USA
Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
International Agency for Research on Cancer Lyon France
International Organization for Cancer Prevention and Research Belgrade Serbia
Kurchatov Scientific Center Moscow Russian Federation
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
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
School of Public Health The University of Queensland Brisbane Australia
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
University of Cambridge Cambridge UK
UPMC Univ Paris 06 Institut Universitaire de Cancérologie Paris France
Van Andel Research Institute Center for Cancer Genomics and Quantitative Biology Grand Rapids MI USA
References provided by Crossref.org
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- $a Machiela, Mitchell J $u Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA.
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- $a Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma / $c MJ. Machiela, JN. Hofmann, R. Carreras-Torres, KM. Brown, M. Johansson, Z. Wang, M. Foll, P. Li, N. Rothman, SA. Savage, V. Gaborieau, JD. McKay, Y. Ye, M. Henrion, F. Bruinsma, S. Jordan, G. Severi, K. Hveem, LJ. Vatten, T. Fletcher, K. Koppova, SC. Larsson, A. Wolk, RE. Banks, PJ. Selby, DF. Easton, P. Pharoah, G. Andreotti, LEB. Freeman, S. Koutros, D. Albanes, S. Mannisto, S. Weinstein, PE. Clark, TE. Edwards, L. Lipworth, SM. Gapstur, VL. Stevens, H. Carol, ML. Freedman, MM. Pomerantz, E. Cho, P. Kraft, MA. Preston, KM. Wilson, JM. Gaziano, HS. Sesso, A. Black, ND. Freedman, WY. Huang, JG. Anema, RJ. Kahnoski, BR. Lane, SL. Noyes, D. Petillo, LM. Colli, JN. Sampson, C. Besse, H. Blanche, A. Boland, L. Burdette, E. Prokhortchouk, KG. Skryabin, M. Yeager, M. Mijuskovic, M. Ognjanovic, L. Foretova, I. Holcatova, V. Janout, D. Mates, A. Mukeriya, S. Rascu, D. Zaridze, V. Bencko, C. Cybulski, E. Fabianova, V. Jinga, J. Lissowska, J. Lubinski, M. Navratilova, P. Rudnai, N. Szeszenia-Dabrowska, S. Benhamou, G. Cancel-Tassin, O. Cussenot, HB. Bueno-de-Mesquita, F. Canzian, EJ. Duell, B. Ljungberg, RT. Sitaram, U. Peters, E. White, GL. Anderson, L. Johnson, J. Luo, J. Buring, IM. Lee, WH. Chow, LE. Moore, C. Wood, T. Eisen, J. Larkin, TK. Choueiri, GM. Lathrop, BT. Teh, JF. Deleuze, X. Wu, RS. Houlston, P. Brennan, SJ. Chanock, G. Scelo, MP. Purdue,
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- $a 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.
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