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

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Date
2017-11Author
Machiela, MJ
Hofmann, JN
Carreras-Torres, R
Brown, KM
Johansson, M
Wang, Z
Foll, M
Li, P
Rothman, N
Savage, SA
Gaborieau, V
McKay, JD
Ye, Y
Henrion, M
Bruinsma, F
Jordan, S
Severi, G
Hveem, K
Vatten, LJ
Fletcher, T
Koppova, K
Larsson, SC
Wolk, A
Banks, RE
Selby, PJ
Easton, DF
Pharoah, P
Andreotti, G
Freeman, LEB
Koutros, S
Albanes, D
Mannisto, S
Weinstein, S
Clark, PE
Edwards, TE
Lipworth, L
Gapstur, SM
Stevens, VL
Carol, H
Freedman, ML
Pomerantz, MM
Cho, E
Kraft, P
Preston, MA
Wilson, KM
Gaziano, JM
Sesso, HS
Black, A
Freedman, ND
Huang, W-Y
Anema, JG
Kahnoski, RJ
Lane, BR
Noyes, SL
Petillo, D
Colli, LM
Sampson, JN
Besse, C
Blanche, H
Boland, A
Burdette, L
Prokhortchouk, E
Skryabin, KG
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, HB
Canzian, F
Duell, EJ
Ljungberg, B
Sitaram, RT
Peters, U
White, E
Anderson, GL
Johnson, L
Luo, J
Buring, J
Lee, I-M
Chow, W-H
Moore, LE
Wood, C
Eisen, T
Larkin, J
Choueiri, TK
Lathrop, GM
Teh, BT
Deleuze, J-F
Wu, X
Houlston, RS
Brennan, P
Chanock, SJ
Scelo, G
Purdue, MP
Type
Journal Article
Metadata
Show full item recordAbstract
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 2 >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.
Collections
Subject
Leukocytes
Telomere
Humans
Carcinoma, Renal Cell
Kidney Neoplasms
Genetic Predisposition to Disease
Odds Ratio
Risk Assessment
Risk Factors
Case-Control Studies
Phenotype
Polymorphism, Single Nucleotide
Genome-Wide Association Study
Mendelian Randomization Analysis
Telomere Homeostasis
Research team
Melanoma and Kidney Cancer
Cancer Genomics
Language
eng
Date accepted
2017-07-17
License start date
2017-11
Citation
European urology, 2017, 72 (5), pp. 747 - 754