Elsevier

European Urology

Volume 72, Issue 5, November 2017, Pages 747-754
European Urology

Platinum Priority – Kidney Cancer
Editorial by Jozefina Casuscelli and A. Ari Hakimi on pp. 755–756 of this issue
Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

https://doi.org/10.1016/j.eururo.2017.07.015Get rights and content

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.

Introduction

Telomeres are TTAGGG nucleotide repeats and a protein complex at chromosome ends that play an essential role in maintaining chromosomal stability. Due to the inability of DNA polymerase to fully extend 3′ DNA ends, telomeres become gradually shorter with each cell division in the absence of telomerase activity [1]. Although in normal cells critically short telomeres will trigger cellular senescence and death, cancer cells can continue to divide despite telomere shortening and the resultant genomic instability [2]. Alternatively, upregulated telomerase activity leading to increased telomere length may also promote tumorigenesis by conferring properties of immortal growth [3]. Indeed, recent studies suggest longer telomere length may be a risk factor for select tumor types including melanoma, lung cancer, chronic lymphocytic leukemia, glioma, and ovarian cancer [4], [5], [6], [7].

As such, relative telomere length in peripheral blood leukocytes has been evaluated in numerous population-based studies as a suspected marker of cancer risk [8]. Most of these studies have characterized telomere length using multiplex quantitative polymerase chain reaction (qPCR) assays [9]. Results of studies of leukocyte telomere length and risk of renal cell carcinoma (RCC) have been inconsistent. Two small hospital-based case-control studies reported inverse associations between telomere length and risk of RCC [10], [11], whereas no significant evidence of an association was observed in a larger population-based case-control study [12] and two cohort-based investigations using prediagnostic samples [13], [14]. In contrast, longer leukocyte telomere length has been associated with reduced RCC survival [15]. Telomerase activity is elevated in renal tumors compared with adjacent normal renal tissue and has been associated with clinicopathologic features of advanced disease [16], [17].

These previous studies have several limitations. Leukocyte telomere length measurements in case-control studies, using postdiagnosis blood samples, may have been influenced by effects of the disease. All studies measured telomere length from a single time point, which may not adequately reflect telomere length status in the etiologically relevant time window, and were susceptible to confounding from RCC risk factors that may be associated with telomere length such as smoking [13], [18] and obesity [19]. Furthermore, qPCR-based measurements of telomere length are sensitive to preanalytic factors such as DNA source material and extraction method [12], [20], [21].

Nine common genetic variants have been identified in genome-wide association studies (GWAS) that are associated with leukocyte telomere length at a level of genome-wide significance (p < 5 × 10−8) [22], [23], [24]. Recent studies have evaluated the relationship between these genetic proxies of telomere length and risk of cancer and found evidence suggesting longer genetically inferred telomere length is associated with increased cancer risk [4], [5], [6], [7]. The approach employed by these studies, Mendelian randomization, uses genetic variants associated with leukocyte telomere length as genetic instruments to investigate the relationship between leukocyte telomere length and RCC risk. For resulting effect estimates to have a valid causal interpretation, several conditions must hold: (1) the telomere length associated variants must be associated with telomere length in circulating leukocytes, (2) the telomere length-associated variants should not be associated with other factors that are associated with telomere length and RCC risk, and (3) the telomere length associated variants can only influence RCC risk by their effect on telomere length, that is they cannot have pleiotropic effects. An advantage of this approach is that it is not susceptible to the biases associated with measured telomere length as described above. A recent investigation surveying several chronic conditions suggested a marginal positive association (p = 0.01) between genetically predicted telomere length and RCC risk, although the sample size was smaller (N = 2461 RCC cases) [7].

In the present study, we evaluated RCC risk in relation to individual telomere length-related genetic variants and an aggregate genetic risk score (GRS) of telomere length-associated genetic variants in a large sample of six RCC GWAS datasets combined by meta-analysis to investigate a potential etiologic relationship between telomere length and RCC risk. We evaluated whether a genetic profile that is associated with longer telomere length is associated with risk of overall RCC and RCC subtypes, and investigated potential modifiers of this relationship.

Section snippets

Material and methods

The RCC GWAS meta-analysis included a total of 10 784 RCC cases and 20 406 controls of European ancestry from six independent scans conducted at the International Agency for Cancer Research (IARC; two scans totaling 5219 RCC cases and 8011 cancer-free controls; analyzed as a combined dataset), the MD Anderson Cancer Center (893 RCC cases, 556 cancer-free controls), the US National Cancer Institute (NCI-1: 1311 RCC cases, 3424 cancer-free controls; NCI-2: 2417 RCC cases, 4391 cancer-free

Results

Associations between the telomere length-associated variants and RCC risk are reported in Table 1 and Supplementary Figure 1. Of the nine telomere length-associated variants, five variants (rs10936599, rs2736100, rs9420907, rs8105767, and rs6772228) displayed evidence for an individual association with RCC risk (p < 0.05) and three (rs10936599, rs2736100, rs9420907) were associated at Bonferroni corrected levels (p < 0.006). This is substantially more than the number of telomere length variants

Discussion

Our findings suggest that an excess of telomere length-related variants is associated with RCC risk and, in aggregate, a genetic risk score predicting longer telomere length in peripheral blood leukocytes is strongly associated with increased RCC risk. The association between longer genetically-predicted telomere length and RCC risk remained statistically significant even after removing two telomere length associated variants highly correlated with GWAS-identified RCC risk variants from the

Conclusions

Our investigation adds to the growing body of evidence indicating some aspect of telomere length is important for the development of a variety of common cancer types suggesting clinicians weigh the potential increases in cancer risk when considering treatments with telomerase activating properties. Future studies are needed to decipher which components of telomere biology, whether it be telomere length, telomerase activity, or an altogether unknown mechanism, are biologically important in

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