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

Dr. Raviprakash Tumkur Sitaram, DVM, MVSc, PhD
Dr. Raviprakash Tumkur Sitaram, DVM, MVSc, PhD
Umeå University
Umeå, Vasterbotten | Sweden
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

Eur Urol 2017 11 7;72(5):747-754. Epub 2017 Aug 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA. Electronic address:

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 (R>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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November 2017
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