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. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: J Neurooncol. 2019 Feb 22;142(3):479–487. doi: 10.1007/s11060-019-03119-w

Longer genotypically-estimated leukocyte telomere length is associated with increased meningioma risk

Ivo S Muskens 1,2, Helen M Hansen 3, Ivan V Smirnov 3, Annette M Molinaro 4, Melissa L Bondy 5, Joellen M Schildkraut 6, Margaret Wrensch 3,4, Joseph L Wiemels 2,3, Elizabeth B Claus 1,7,*
PMCID: PMC6482066  NIHMSID: NIHMS1522445  PMID: 30796745

Abstract

Purpose:

Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls.

Methods/patients:

One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP’s genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates.

Results:

Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR: 1.14, 95%-CI: 1.01–1.28, rs2736100: OR: 1.13, 95%-CI: 1.03–1.25, rs9420907: OR: 1.22, 95%-CI: 1.07–1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05bp), mean controls: 541.5 bp (SE: 2.02bp), logistic regression p-value = 2.13×10−5].

Conclusion:

Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.

Keywords: Leukocyte telomere length, meningioma, mendelian randomization, risk

Introduction

The telomerase complex is a group of protein subunits which build repeat sequence “caps” at the end of chromosomes.[1, 2] These caps consist of “TTAGGG” sequences to maintain telomere length, sustain renewability of cells, and prevent apoptosis.[3, 4] Telomere length varies among individuals.[5] Longer leukocyte telomere length (LTL) has been associated with longer lifespan and may also play a role in ageing,[5, 6] while shorter LTL has been associated with various age-related diseases including type 2 diabetes and cardiovascular disease.[7–11] LTL is partially genotypically determined by polymorphisms in the genes that code for protein members of the telomerase enzyme complex.[5] Longer genotypically-estimated LTL has been associated with increased risk of various cancers including B-cell lymphoma and leukemia, and also non-hematopoietic tumors such as glioma and neuroblastoma.[12–19] LTL, measured in blood, is correlated with telomere length in other body tissues.[20]

The underlying genetic basis for the genesis and recurrence of meningioma is still relatively poorly understood, although variations in the 10p12.31 and 11p15.5 regions have been associated with increased meningioma risk.[21, 22] Germline mutations in the TERT gene (located on 5p15.33) and its promotor have been associated with several malignancies and intracranial tumors.[3, 4, 23–26] Somatic TERT promotor mutations in glioma have been associated with greater telomerase activity,[27] up-regulation of TERT,[24] and even decreased survival.[28] Somatic TERT promotor mutations have also been associated with malignant progression of meningiomas.[29, 30] Furthermore, increased TERT activity in meningioma has been associated with higher WHO grade and poorer outcome.[23] Given the suggestion that TERT genes may play a role in meningioma risk and progression, we utilized a targeted panel of telomerase genes to formally assess the association between impactful telomerase gene variants in a large sample of meningioma cases and controls.

Methods

Ethics statement:

This multi-center study was approved by the Yale University, Duke University, M.D.Anderson Cancer Center, the University of California, San Francisco, and the Brigham and Woman’s Hospital institutional review boards. Written informed consent was obtained from all study participants.

Lymphocyte telomere length:

Eight SNPs previously significantly associated with LTL[13] were assessed. These SNPs were located on genes ACYP2 (rs11125529), TERC (rs10936599), NAF1 (rs7675998), TERT (rs2736100), OBFC1 (rs9420907), CTC1 (rs3027234), ZNF08 (rs8105767), and RTEL1 (rs755017), and were compared between meningioma cases and controls individually, and also combined together within a weighted genetic risk score. Individual SNP tests were performed using SNPTEST v2.5.4 under an additive frequentist model with gender and the first two ancestral principal component included as covariates.[13, 31, 32]

The genotypically-estimated LTL was estimated by summing the number of base pairs per affected allele for each sample and could, therefore, range from 0 to 1215 bp. The number of base pairs per alternate allele are described in table 1. The difference in genotypically-estimated LTL was compared between the meningioma cases and controls using a two-sample t-test (Welch’s), box and whisker plots, and logistic regression with sex, the first two ancestral principal components, and the genotyping panel (Goldengate or Axiom, see below) as covariates. Odds ratios (ORs) were calculated per 50 bp increase of genotypically-estimated LTL. A separate model that also included age was constructed without controls form the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) study as age was not available for these samples.

Table 1:

Number of base pair effect per allele included in the analysis based on data by the ENGAGE Consortium.[13]

SNP Chromosome Gene Effect allele Base Pairs* EAF cases (%) EAF controls (%) Allelic OR 95%-CI P-value**
rs11125529 2 ACYP2 A 66.9 12.7 13.3 0.95 0.82–1.10 0.49
rs10936599 3 TERC C 117.3 24.4 22.2 1.14 1.01–1.28 0.02
rs7675998 4 NAF1 G 89.7 21.7 21.7 1.00 0.89–1.13 0.94
rs2736100 5 TERT C 94.2 52.3 49.0 1.13 1.03–1.25 0.01
rs9420907 10 OBFC1 C 82.8 16.7 14.1 1.22 1.07–1.39 0.003***
rs3027234 17 CTC1 C 25.2 21.7 22.3 0.97 0.86–1.08 0.55
rs8105767 19 ZNF208 G 57.6 30.4 28.7 1.08 0.97–1.20 0.15
rs755017 20 RTEL1 G 74.1 13.5 12.1 1.15 1.00–1.33 0.05
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*

Number of base pairs the affected allele increases the genotypically-estimated leukocyte telomere length (LTL)[13, 32]

**

p-value for risk for meningioma under an additive frequentist model

***

Significant after correction for multiple testing (eight degrees of freedom).

Abbreviations: EAF: estimated allele frequency; bp: base pairs, OR: odds ratio, LTL: Leukocyte telomere length.

Subjects:

Subjects were non-Hispanic white ancestry to eliminate interference from population substructure. Two datasets were constructed and then merged together. The first dataset is a convenience sample of 244 persons who underwent surgery for an intracranial meningioma at Brigham and Women’s Hospital and 1141 controls from the San Francisco Adult Glioma Study which were sequenced for a panel of 953 telomere gene-related SNPs and were genotyped using Illumina GoldenGate® genotyping chemistry.[33] The second dataset consisted of 809 cases and 798 controls from the population-based Meningioma Consortium Case/Control Study[34] along with 2498 additional controls from the RPGEH study were genotyped using Affymetrix Axiom CEU World array as described elsewhere.[21, 35]

Imputation and merging datasets.

Both the Goldengate genotyped and Axiom genotyped subjects were imputed, separately, to ascertain all genotypes. The Goldengate array had rs11125529, rs10936599, rs2736100, rs9420907, rs3027234, and rs755017 on the array, and rs7675998 and rs8105767 were imputed. The Axiom array had all SNPs imputed (rs11125529, rs10936599, rs2736100, rs7675998, rs9420907, rs3027234, rs8105767, and rs755017). Imputation was performed using Minimac3 2.0.1 with the reference panel from the Haplotype Reference Consortium.[36] Imputation accuracy was determined by Pearson correlation (squared) between genotyped loci, and the same loci after being masked and imputed. A forest plot depicting the odds ratios (ORs) with 95%-CI of these 8 SNPs for meningioma case-control status was constructed in R. The data will be made available through dbGAP at a later point.

Results

The genotypes of the 8 SNPs in meningioma cases vs controls:

Three out of the eight evaluated SNPs were nominally significantly associated with increased meningioma risk (rs10936599: OR: 1.14, 95%-CI: 1.01–1.28, rs2736100: OR: 1.13, 95%-CI: 1.03–1.25, rs9420907: OR: 1.22, 95%-CI: 1.07–1.39, Table 1, Figure 1). Only rs9420907 remained significant with p=0.003 after application of Bonferroni correction based on 8 comparisons.

Figure 1: Forest plot depicting the association between the genotypically-estimated LTL associated SNPs and case-control status.

Figure 1:

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Odds ratios with confidence intervals for the association between the SNPs and meningioma case-control status were calculated under an additive frequentist model and were corrected for gender and the first two principal components. Abbreviations: SNP: Single nucleotide polymorphism; OR: odds ratio, CI: confidence interval.

Genotypically-estimated LTL:

The mean genotypically-estimated LTL was 560.2 bp (standard error (SE): 4.05bp) for cases compared to 541.5 bp (SE: 2.02bp) for controls (p-value T-test: 3.62×10−5, OR per 50 bp increase in genotypically-estimated LTL: 1.06, 95%-CI: 1.03–1.09, logistic regression p-value = 2.13×10−5, Figure 2). Using quintiles of genotypically-estimated LTL based on controls, the odds ratio for meningioma increased with higher quintiles, with the highest quintile having significantly higher risk compared to the median quintile (OR: 1.28, 95%-CI: 1.04–1.58, p = 0.02, Figure 3). An additional model that also incorporated age constructed showed a very similar effect measure (OR per 50 bp increase in genotypically-estimated LTL: 1.06, 95%-CI: 1.03–1.10, logistic regression p-value = 7.31×10−5 with exclusion of RPGEH controls).

Figure 2: Boxplots for genotypically-estimated leukocyte telomere length and meningioma case-control status by sequencing panel.

Figure 2:

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The boxplots depicting the distribution of genotypically-estimated leukocyte telomere length (LTL) in meningioma patients and controls. Separate boxplots are depicted for the who different sample sources and overall. The p-values were 0.0009, 0.003, 2.13×10−5 for the telomere SNP panel, the meningioma consortium, and overall in a logistic regression model with gender and the first two ancestral principal components as covariates. The model for the overall analysis was also corrected for sequencing panel used.

Figure 3: Effect of increasing quintile of genotypically-estimated LTL on meningioma risk.

Figure 3:

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The odds ratios are relative to the median (third) quintile. Quintiles were defined based on genotypically-estimated LTL in controls. The vertical bars correspond to 95% confidence intervals. Odds ratios are corrected for the first two ancestral principal components, study, and sex.

When stratified by sex, the association was strongly significant in females and borderline significant in males (females: OR per 50 bp increase in genotypically-estimated LTL: 1.07, 95%-CI: 1.03–1.10, p-value = 9.58×10−5, males: OR per 50 bp increase in genotypically-estimated LTL: 1.04, 95%-CI: 1.00–1.09, p-value = 0.06). As rs2736100 had the lowest r2 of 0.53 (all other SNPs had an r2 greater than 0.8), the analysis was rerun using the remaining 7 SNPs. The association remained significant (OR per 50 bp increase in genotypically-estimated LTL: 1.05, 95%-CI: 1.02–1.08, p-value: 0.001). An analysis for the same 7 SNPs by sex showed that the association was significant in females but not in males (females: OR per 50 bp increase in genotypically-estimated LTL: 1.06, 95%-CI: 1.02–1.10, p-value = 0.002, males: OR per 50 bp increase in genotypically-estimated LTL: 1.03, 95%-CI: 0.98–1.09, p-value = 0.22).

Discussion

This is the first study to evaluate the relationship between genotypically-estimated LTL and meningioma risk, finding a positive association. Longer telomeres allow for more cell divisions before replicative senescence is reached and may therefore result in occurrence of mutations that allow cells to grow indefinitely and undergo malignant transformation.[19] Longer genotypically-estimated LTL based on the same SNPs used in this analysis has previously also been associated with increased risk of development of both glioma and chronic lymphocytic leukemia.[12, 37] However, longer LTL measured before ovarian cancer diagnosis has also been associated with a decreased risk of development of ovarian cancer.[38] Nevertheless, our finding that increased genotypically-estimated LTL is associated with meningioma case-control status is consistent with most other malignancies.

Reproducible genetic findings on meningioma were not reported until recent GWAS studies found associations on 10p12 and 11p15.[21, 22, 39] The alleles assessed for the current study do not have any linkage with those two known GWAS hits, nor do the known meningioma GWAS hits have any known impact on telomere length or function. The most significant gene here, OBFC1, is on chromosome 10q24, distant from the MLLT10 GWAS hit on 10p12. [21, 22] OBFC1 is part of the CST complex which helps to maintain telomere length.[40] This complex is also involved in DNA replication (DNA polymerase priming), and therefore a specific role in meningioma apart from telomere length maintenance is possible. The SNPs assessed here impart small effects which are not individually significant in any current GWAS analysis but collectively represent a phenotype contributing to genetic risk of meningioma. This analysis is a testament to the power of using combined genetic summary variables (such as polygenic risk scores and Mendelian randomization) to discover genetic based traits that impact risk of meningioma and other diseases.

This is the first study to evaluate telomere length for association with meningioma. The sample size is relatively large and the data primarily population-based, allowing for generalization of our results. The strength of using genetic variants to estimate LTL lies in the fact that genetics are determined at birth and are not influenced by external factors known to influence telomere length (e.g. age and smoking).[20, 41] Genotypically-estimated LTL does, therefore, not have to be controlled for confounding or reverse causation.

This study is also limited by several factors. Genotypically-estimated LTL is only a partial substitute for meningeal telomere length, explains a small proportion (approximately 1.23%) of variance in LTL, and is measured in leukocytes rather than meninges or their precursor cells.[13] Pleiotropy can never be truly excluded as the calculated genotypically-estimated LTL variable may reflect a different underlying disease process and act as a biomarker. It was not possible to do subgroup analyses for tumor location due to limitations of the data. The cases and controls in this study were all from Western European descent, which limits the implications of this study for other ethnicities. Therefore, further studies in other ethnicities are warranted, in particular for African Americans who suffer a 20% higher rate of meningioma compared to those of Western European descent.[42]

Acknowledgements:

The authors would like to thank all the participants in this study.

Disclosures: This work was supported by NIH R01 grants CA109468, CA109461, CA109745, CA109473, CA109475; CA52689, NIH R25 grant CA112355, NIH P50 grant CA097257, as well as by the Brain Science Foundation, the Meningioma Mommas, and the University of California, San Francisco Lewis Chair in Brain Tumor Research (MW).

Footnotes

Conflict of Interest: The authors declare that they have no conflict of interest.

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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