Platinum Priority – Kidney CancerEditorial by Jozefina Casuscelli and A. Ari Hakimi on pp. 755–756 of this issueGenetic Variants Related to Longer Telomere Length are Associated with Increased Risk of 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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Association between telomere length and mitochondrial copy number and cancer risk in humans: A meta-analysis on more than 300,000 individuals
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2020, GeneCitation Excerpt :For urinary cancer, there are multiple factors which influence the risk of tumorigenesis. For example, ethnicity is a key factor in PCa, there is a higher incidence of PCa in African than Caucasian; Smoking habits will lead to a bad consequences of bladder cancer; genetic variants which located on longer telomere length are related to an enhanced risk of renal cell carcinoma (RCC), and there are several other factors, including aging, gender, androgen and etc. (Odedina et al., 2009; Protzel et al., 2012; Grossmann et al., 2013; Rink et al., 2015; Li et al., 2017; Machiela et al., 2017; Siegel et al., 2018). The variants of BIRC5 is reported closely associated with the risk of RCC.
Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients
2020, EBioMedicineCitation Excerpt :In addition, numerous studies have shown that leukocyte telomere length (LTL) is associated with the risks of different cancers. Earlier retrospective case control studies suggested that short LTL was a risk factor for a few cancers [11–16], but later prospective studies and recent Mendelian randomization studies using genetically predicted LTL have increasingly found that long LTL was a risk factor for a number of cancers, including B-cell lymphoma, melanoma, lung adenocarcinoma, neuroblastoma, adult glioma, meningioma, renal cell carcinoma, and osteosarcoma [17–31]. Mendelian randomization (MR) uses genetic determinants of an exposure or intermediate biomarker to investigate the potential causal relationship between the interested exposure or biomarker with a disease outcome [32].
The TERT locus genotypes of rs2736100-CC/CA and rs2736098-AA predict shorter survival in renal cell carcinoma
2019, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :In a recent study, de Martino et al. [27] compared the rs2736100 and rs2736098 SNPs between RCC and HCs, and observed that the rs2736098 AA genotype increased the RCC risk, but rs2736100 did not. However, Machiela et al. showed an intimate association between rs2736100-C and RCC susceptibility [17]. In our study, there was no significant association between either rs2736098 or rs2736100 and the RCC risk.
CAV1 polymorphisms rs1049334, rs1049337, rs7804372 might be the potential risk in tumorigenicity of urinary cancer: A systematic review and meta-analysis
2019, Pathology Research and PracticeCitation Excerpt :There are ∼204,360 new diagnosed urinary cancers in 2014, account for about 5.65% of all new diagnosed cancers [3]. Well known, urinary cancer are multifactorial disease effected by genetic variants, aging, ethnicity, gender, smoking, androgen and etc. [1,4–9]. Genetic variants may be an important contributor to the risk of urinary cancer.