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Meta-Analysis
. 2017 Nov;72(5):747-754.
doi: 10.1016/j.eururo.2017.07.015. Epub 2017 Aug 7.

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

Mitchell J Machiela  1 Jonathan N Hofmann  1 Robert Carreras-Torres  2 Kevin M Brown  1 Mattias Johansson  2 Zhaoming Wang  3 Matthieu Foll  2 Peng Li  2 Nathaniel Rothman  1 Sharon A Savage  1 Valerie Gaborieau  2 James D McKay  2 Yuanqing Ye  4 Marc Henrion  5 Fiona Bruinsma  6 Susan Jordan  7 Gianluca Severi  8 Kristian Hveem  9 Lars J Vatten  10 Tony Fletcher  11 Kvetoslava Koppova  12 Susanna C Larsson  13 Alicja Wolk  13 Rosamonde E Banks  14 Peter J Selby  14 Douglas F Easton  15 Paul Pharoah  15 Gabriella Andreotti  1 Laura E Beane Freeman  1 Stella Koutros  1 Demetrius Albanes  1 Satu Mannisto  16 Stephanie Weinstein  1 Peter E Clark  17 Todd E Edwards  17 Loren Lipworth  17 Susan M Gapstur  18 Victoria L Stevens  18 Hallie Carol  19 Matthew L Freedman  19 Mark M Pomerantz  19 Eunyoung Cho  20 Peter Kraft  21 Mark A Preston  22 Kathryn M Wilson  21 J Michael Gaziano  23 Howard S Sesso  21 Amanda Black  1 Neal D Freedman  1 Wen-Yi Huang  1 John G Anema  24 Richard J Kahnoski  24 Brian R Lane  25 Sabrina L Noyes  26 David Petillo  26 Leandro M Colli  1 Joshua N Sampson  1 Celine Besse  27 Helene Blanche  28 Anne Boland  27 Laurie Burdette  1 Egor Prokhortchouk  29 Konstantin G Skryabin  29 Meredith Yeager  1 Mirjana Mijuskovic  30 Miodrag Ognjanovic  31 Lenka Foretova  31 Ivana Holcatova  32 Vladimir Janout  33 Dana Mates  34 Anush Mukeriya  35 Stefan Rascu  36 David Zaridze  35 Vladimir Bencko  37 Cezary Cybulski  38 Eleonora Fabianova  12 Viorel Jinga  37 Jolanta Lissowska  39 Jan Lubinski  40 Marie Navratilova  32 Peter Rudnai  41 Neonila Szeszenia-Dabrowska  42 Simone Benhamou  43 Geraldine Cancel-Tassin  44 Olivier Cussenot  45 H Bas Bueno-de-Mesquita  46 Federico Canzian  47 Eric J Duell  48 Börje Ljungberg  49 Raviprakash T Sitaram  49 Ulrike Peters  50 Emily White  50 Garnet L Anderson  50 Lisa Johnson  50 Juhua Luo  51 Julie Buring  21 I-Min Lee  52 Wong-Ho Chow  4 Lee E Moore  1 Christopher Wood  53 Timothy Eisen  54 James Larkin  55 Toni K Choueiri  19 G Mark Lathrop  56 Bin Tean Teh  26 Jean-Francois Deleuze  57 Xifeng Wu  4 Richard S Houlston  58 Paul Brennan  2 Stephen J Chanock  1 Ghislaine Scelo  2 Mark P Purdue  59
Affiliations
Meta-Analysis

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

Mitchell J Machiela et al. Eur Urol. 2017 Nov.

Erratum in

  • Corrigendum re "Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma" [Eur Urol 2017;72:747-54].
    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 WY, 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 HBA, Canzian F, Duell EJ, Ljungberg B, Sitaram RT, Peters U, White E, Anderson GL, Johnson L, Luo J, Buring J, Lee IM, Chow WH, Moore LE, Wood C, Eisen T, Larkin J, Choueiri TK, Lathrop GM, Teh BT, Deleuze JF, Wu X… See abstract for full author list ➔ Machiela MJ, et al. Eur Urol. 2018 Sep;74(3):e85-e86. doi: 10.1016/j.eururo.2018.05.017. Epub 2018 May 28. Eur Urol. 2018. PMID: 29853305 Free PMC article. No abstract available.

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.

Keywords: Genetic variants; Mendelian randomization; Renal cell carcinoma; Risk; Telomere length.

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Figures

Fig. 1
Fig. 1
Forest plot for associations of the telomere length associated genetic risk score with renal cell carcinoma risk. Odds ratios are scaled to predicted kilobase increase in telomere length. Combined association p <0.0001. Heterogeneity p =0.96. FE = fixed effects; IARC = International Agency for Cancer Research; MDA = MD Anderson Cancer Center; NCI = National Cancer Institute.
Fig. 2
Fig. 2
Associations of telomere length genetic risk score (GRS) decile with renal cell carcinoma. Dashed line represents the baseline for the reference decile (lowest decile). Error bars represent 95% confidence intervals around the odds ratio association for each GRS decile and renal cell carcinoma.
Fig. 3
Fig. 3
The effect of each variant on telomere length and renal cell carcinoma (RCC) risk. Estimates for the single nucleotide polymorphism (SNP)--telomere and SNP--RCC associations are presented in Table 1. Error bars around each estimate are 95% confidence intervals around the β estimate. A best fit regression line (dashed line) and 95% confidence interval (shaded region) are plotted using the likelihood based estimate (odds ratio =2.00, 95% confidence interval = 1.64–2.43, p < 0.0001).

Comment in

References

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