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Clin Cancer Res. Author manuscript; available in PMC May 1, 2011.
Published in final edited form as:
PMCID: PMC2989876
EMSID: UKMS32003

Genetic risk profiles identify different molecular etiologies for glioma

Abstract

Purpose

Genome-wide association studies have recently identified single nucleotide polymorphisms in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1) and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Since gliomas are heterogeneous in histology, molecular alterations and clinical behavior we have investigated these polymorphisms for potential correlations with tumor histology and patient survival.

Experimental Design

We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients as well as the relationship between SNP-genotype and overall survival.

Results

In both cohorts the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001) while rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variation at these loci have sub-type specific effects on the risk of developing glioma. In contrast rs4977756 genotype was not correlated with tumor grade consistent with the causal variant having a generic influence on glioma development. None of the five SNPs were associated with prognosis, independent of tumor grade.

Conclusions

Our findings provide novel insight into etiological pathways in the different glioma subtypes.

Keywords: genetic risk, glioma, glioblastoma, SNP, genetic polymorphism

Introduction

Glioma comprises ~40% of all primary brain tumors, accounting for ~13,000 deaths in the US each year. Most are associated with a poor prognosis irrespective of clinical care with the most common type of glioma, glioblastoma (GBM), having a median overall survival of only 10-15 months(1-3).

We have recently performed a genome-wide association (GWA) study of glioma based on 1,878 cases and 3,670 controls. The most significant associations seen in the GWA study were validated in three independent case-control series including a French and German cohort. Single nucleotide polymorphisms (SNPs) mapping to five loci were shown to confer a small but significant risk of glioma: 1). rs2736100 which localizes to intron 2 of the TERT gene at 5p15.33, 2). rs4295627 mapping to intron 3 of CCDC26 at 8q24.21. 3). rs4977756 mapping 59kb telomeric to CDKN2B within a 122-kb region of linkage disequilibrium (LD) at 9p21.3 which also incorporates CDKN2A. 4). rs6010620 mapping to a 65kb region of LD at 20q13.33 to which the RTEL1 gene maps. 5). rs498872 maps to the 5′-UTR of the PHLDB1 gene at 11q23.3(4). A parallel study by Wrensch et al. provided additional and independent evidence for a role of loci at 9p21 near CDKN2B and for rs6010620 at 20q13.3 as genetic risk factors for glioma development(5).

Various glioma subtypes defined in part by malignancy grade (e.g. pilocytic astrocytomas WHO grade I, diffuse ‘low grade’ gliomas WHO grade II, anaplastic gliomas WHO grade III, and GBM WHO grade IV) can be distinguished. Accumulating data indicate that the subtypes of glioma have different molecular genetic profiles possibly resulting from different etiologic pathways, which might be shared by different tumor subtypes or be type specific(2, 3, 6). This raises the possibility that susceptibility loci for glioma may influence a specific glioma subtype.

To examine this proposition we have examined the association between the five glioma risk SNPs and clinico-pathological data in the French and an extended German patient series as part of the above-mentioned GWA study. Our findings show that genetic risk profiles are different between glioma subtype and correlate with tumor grade, compatible with differential pathogenetic roles for the five genetic loci.

Material and Methods

Patients

We studied a subset of the French and German patients, which presented to the respective institution for primary treatment; for which complete follow-up data was available and that had been originally genotyped as part of our GWA study of glioma previously reported(4).

The French glioma cases come from a systematic series of 1,391 patients with histologically proven glioma registered with the Service de Neurologie “Mazarin”, Groupe Hospitalier Pitié-Salpêtrière Paris. The German cases come from a series of 805 consecutive patients who underwent surgery in the Department of Neurosurgery of the University Hospital of Bonn between 1996 and 2008. The histological diagnoses were made at the Department of Neuropathology “R. Escourolle”, Groupe Hospitalier Pitié-Salpêtrière, Paris and at the Institute for Neuropathology/German Brain Tumor Reference Center, University of Bonn Medical Center.

Clinical data were retrieved from prospectively maintained databases in Paris and Bonn, and were centrally harmonized. Clinical data used included: age at surgery, preoperative Karnofsky performance index (KPI), sex, histology (pilocytic astrocytoma WHO grade I, ganglioglioma WHO grade I, astrocytoma WHO grade II, oligodendroglioma/ oligoastrocytoma WHO grade II, anaplastic astrocytoma WHO grade III, anaplastic oligodendroglioma/ oligoastrocytoma WHO grade III, GBM WHO grade IV), degree of resection (complete, incomplete, biopsy), postoperative radiotherapy and chemotherapy.

Table 1 provides a detailed description of the clinico-pathological characteristics of the patients (913 from France and 664 from Germany). Differences in patient characteristics between the two cohorts are reflective of differences in referral patterns between the clinical centers.

Table 1
Demographic and clinical characteristics of the patient cohorts. (a) French and (b) German

Collection of blood samples and clinico-pathological information was undertaken with informed consent and relevant ethical review board approval in accordance with the tenets of the Declaration of Helsinki.

Genotyping

Genotyping procedures have previously been described(4). Briefly, DNA was extracted from samples using conventional methodologies and quantified using PicoGreen (Invitrogen, Carlsbad, USA). Genotyping of the French series of glioma cases was conducted using single-base primer extension chemistry MALDI-TOF MS detection (Sequenom, San Diego, USA; http://www.sequenom.com/). Competitive allele-specific PCR KASPar chemistry (KBiosciences Ltd, Hertfordshire, UK; http://kbioscience.co.uk/). was used to genotype the German glioma cases. All primers and probes used are available on request. Genotyping quality control was evaluated through inclusion of duplicate DNA samples in SNP assays. For all SNP assays >99% concordant results were obtained. Samples having SNP call rates <90% were excluded from the analysis.

Statistical analyses

Statistical analyses were undertaken using R software. Differences in the distribution of categorical variables were analyzed using logistic regression. The R suite can be found at http://www.r-project.org/.

Overall survival (OS) of patients was the end point of the analysis. Survival time was calculated from the date of diagnosis of glioma to the date of death. Patients who were not deceased were censored at the date of last contact. Mean follow-up time was computed among censored observations only. Kaplan-Meier survival curves according to SNP genotype were generated and the homogeneity of the survival curves between genotypes evaluated using the log-rank test. Cox regression analysis was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CI) while adjusting for age, sex, treatment, KPI and histology(7).

Results

Genetic risk profiles differ between glioma subtypes

The genotype frequencies of each of the five SNPs in the two patient cohorts are detailed in Tables Tables22 and and3.3. Also shown are the minor allele frequencies (MAF) of each of the five SNPs in the respective control populations.

Table 2
Correlations between glioma susceptibility alleles and histological categories
Table 3
Correlations between glioma susceptibility alleles and malignancy grades

The German series included a sizable proportion of WHO grade I tumors (i.e. pilocytic astrocytomas and gangliogliomas; n=65). Risk allele frequencies for this category differed for rs2736100 and rs4977756 (P = 0.012 and 6.34 × 10−3) from diffuse gliomas WHO grade II-IV. The proportion of WHO grade I gliomas in the French series was too low to confirm or refute this finding (Tables (Tables22 and and3).3). There were no significant associations between the risk alleles tested and oligodendroglial histology in either cohort.

The carrier frequencies of the risk alleles for the TERT and RTEL1 SNPs, rs2736100 and rs6010620, were strongly correlated with the diagnosis of GBM in both the French and the German case series (TERT: P = 7.78 × 10−4, 1.67 × 10−3; RTEL1: P = 1.92 × 10−3, 0.017 respectively). In contrast the carrier frequencies of the risk alleles of rs4295627 (CCDC26) and rs498872 (PHLB1) were inversely correlated with GBM histology (CCDC26: P = 9.90 × 10−8, 0.05; PHLDB1: P = 1.92 × 10−3, 6.54 × 10−3). These associations remained significant after adjustment for multiple SNP comparisons (i.e. P < 0.05). No association was seen for the CDKN2A/CDKN2B SNP rs4977756 in either case series (P = 0.82, 0.28; Tables Tables22 and and33).

Furthermore, stratification of tumors by WHO grade showed a strong relationship with four of the SNPs. In both case series the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.05). The strong relationship between TERT and RTEL1 SNPs in both series was primarily driven by significant enrichment of risk alleles associated with GBM. Conversely, rs4295627 and rs498872 risk genotypes were inversely related to WHO tumor grade (P < 0.01). In contrast rs4977756 genotype was not correlated with WHO tumor grade in either case series.

Relationship between genotype and patient survival

The average time at risk amongst the 1,577 glioma patients in both studies was 34 months, with a range of 0 to 25 years. Cases were followed up for a total of 53,948 person-months with the occurrence of 799 deaths from any cause. As expected, survival was significantly poorer for patients with high-grade tumors (P < 0.00001) in both cohorts. Furthermore, sex, age at surgery, preoperative KPI, histology, degree of resection, and adjuvant therapy were also highly correlated with patient outcome on both cohorts (P < 0.01), confirming the prognostic value of these parameters in clinical practice.

Kaplan-Meier estimates showed significant correlations between genotypes and overall survival for rs2736100, rs4295627, and rs498872 in the French series (P = 0.007, 0.006 and 0.029 respectively). Analysis of the German cohort confirmed these findings for rs498872 (P = 0.002) and rs2736100 (P = 0.042). In view of the strong correlation between histology and genotype, we studied the relationship between genotype and survival separately for GBM, anaplastic gliomas WHO grade III, and low grade gliomas WHO grade II. Stratified analysis provided no evidence for an independent relationship between genotype and OS within each of the histological categories in each cohort. Figure 1 shows Kaplan-Meier estimates for overall survival for the combined French and German GBM patients.

Fig. 1
Relationship between overall survival and SNP genotype in combined French and German GBM patients. (a) rs2736100 (TERT), (b) rs4295627 (CCDC26), (c) rs4977756 (CDKN2A/CDKN2B), (d) rs498872 (PHLDB1), (e) rs6010620 (RTEL1)

Within histological categories age, sex, treatment (chemotherapy and radiotherapy), and KPI were predictive of patient outcome. Type of resection was not significantly associated with patient outcome. Survival analysis after adjusting for significant covariates in the French series gave statistically significant per allele HRs for rs4295627 genotypes in the WHO grade II (P = 0.006) cases (Table 4). Similar analysis of the German cohort provided failed to replicate these finding but did show a statistically significant per allele HR for rs6010620 in WHO grade IV patients (P = 0.021; Table 4). Given the number of tests performed and inconsistent results obtained, collectively these data indicate that while common alleles of specific gene loci may modify the risk to be diagnosed with a glioma, they are not a major determinant of the patients’ prognosis beyond the correlation with the WHO grade/GBM histology.

Table 4
Hazard ratios for overall survival of patients with gliomas WHO grades II, III and IV vs. SNP genotypes in the German and French cohorts after adjusting for age, sex, therapy and KPI

Discussion

Here we have shown a strong relationship between common genetic variants predisposing to glioma and tumor phenotype. A major strength of our study is that our analysis has been based on two large independent patient cohorts with detailed clinico-pathological data, allowing for validation of findings and precise estimate of risk by tumor subtype. Furthermore, we have been able to robustly evaluate the relationship between genotype and patient outcome.

While the five SNPs are not necessarily directly causal they map within genes or are in LD blocks containing genes, hence the SNPs are most probably correlated with sequence changes having cis-acting effects on neighbouring genes. As the SNPs are not correlated with known polymorphisms in the coding sequence of respective genes the associations are likely to be mediated through non-coding variation impacting on gene expression.

Four of the five susceptibility loci are highly correlated with tumor subtype, providing evidence that the genetic risk profiles of gliomas differ by histology (i.e. WHO grades). Moreover, findings are consistent with different etiological factors acting through different genetic pathways for the glioma subtypes.

Specifically, our findings implicate genetic variation in TERT and RTEL1 in the development of GBM and possibly malignant glioma progression in general. RTEL1 is critical for telomere replication and the maintenance of genomic integrity by preventing homologous recombination(8). The TERT gene encodes the catalytic subunit of telomerase, essential for telomerase activity. Telomerase activity is a prerequisite for cellular immortalization and telomerase activation is highly correlated with malignancy in glioma and GBM histology(9, 10). In contrast to the TERT and RTEL1 associations, risk alleles of CCDC26 and PHLB1 were correlated with low grade tumors. CCDC26 encodes a retinoic acid-dependent regulator of cell differentiation and death(11). Retinoic acid induces caspase-8 transcription through phosphorylation of CREB and increases apoptosis induced by death stimuli in neuroblastoma(12) and glioblastoma cells through down regulation of telomerase activity(13). The function of PHLDB1 is currently unknown, however the 11q23.3 region is commonly deleted in neuroblastoma, suggesting a role for the gene in neuro-biology(14). Collectively these data are compatible with genetic variation in TERT, RTEL1, CCDC26 and PHLDB1 having a modifier function in tumor development.

The association between rs4977756 (CDKN2A/CDKN2B) and glioma risk is independent of tumor grade. While homozygous deletion and mutation of the CDKN2A/CDKN2B locus is common in glioma especially amongst high grade tumors(6, 15, 16) the role of these genes in glioma is complex as CDKN2A and CDKN2B genes encode functionally different tumor suppressors which interact with both p53- and pRB-dependent cell cycle control pathways controlling senescence, apoptosis and stem cell renewal(17). Whatever the genetic basis of the rs4977756 association the data are consistent with the causal variant at 9p21.3 having a generic effect on tumor development, specifically being compatible with an influence at a progenitor stage in tumorigenesis. This assertion is in keeping with germline mutation in CDKN2A/CDKN2B causing dominantly inherited melanoma-astocytoma syndrome (MIM 155755)(18).

We did not observe any consistent correlation between the TERT, RTEL1, CCDC26, PHLDB1 or CDKN2A/CDKN2B SNP genotypes with patient survival after correction for malignancy grade and treatment. Similarly, Liu et al. observed correlations with overall and/or longterm survival for RTEL1 and CCDC26 SNPs in their glioblastoma patients, but were unable to independently confirm these results in two additional patient cohorts(19). The impact of any single SNP on patient survival is, however a priori at best likely to be modest and our power to demonstrate a less than 5% difference in outcome over 5-years by genotype was <80%. Hence we cannot exclude the possibility that one or more of the SNPs are independently predictive but any association is unlikely to be clinically important in isolation.

In conclusion, we have shown that there is heterogeneity in the risk of different glioma subtypes for common susceptibility alleles. Specifically, our findings support a role for TERT and RTEL1 dependent telomere dynamics in the malignant progression of gliomas (or at least the growth of GBM), and associate two genes with largely unknown functions so far (CCDC26 and PHLDB1) with the development of less aggressive glial tumors. Finally, our results indicate a role for the CDKN2A/CDKN2B locus in gliomas independent of the expression of a malignant phenotype. These findings provide support for the notion that the glioma subtypes result, in part, from different etiologic pathways, and do not merely represent different stages of tumor evolution within a common carcinogenic pathway. The impact of each of these SNPs on tumor biology is small and hence individually they may not have immediate clinical application. However, the observed differences provide novel insights into the biological mechanisms underlying glioma formation and underscore glioma heterogeneity. These data may also aid in the identification of future biomarkers specific for glioma subtypes and tumor grades.

Statement of translational relevance

Genome-wide association studies have recently identified single nucleotide polymorphisms (SNPs) in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1) and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Genetic polymorphisms involved in cancer formation are also candidate clinical biomarkers. The present paper excludes a role for the five SNPs tested as prognostic factors. However, our data also show that there is considerable heterogeneity in the risk of different glioma subtypes and WHO grades for common susceptibility alleles of specific genes. These data provide some support for the notion that the glioma subtypes result, in part, from distinct etiologic pathways, and do not merely represent stages of tumor evolution within a common carcinogenic pathway. Our findings may aid in the identification of future biomarkers specific for glioma subtypes and tumor grades.

Acknowledgments

We are indepted to B. Harzheim (Bonn) and Dr. A. Müller-Erkwoh (Bonn) for help with the acquisition of clinical data. R. Mahlberg (Bonn) provided technical support. Part of the German data form the doctoral thesis of KG.

Funding: This work was supported in part by grants from the Ligue Nationale contre le Cancer and the Institut National du Cancer (INCA; PL 046) in France; and in Germany by grants from the Deutsche Forschungsgemeinschaft (DFG Az Si 552/2) and the University of Bonn (BONFOR O-126.0030) to MSi and the Deutsche Krebshilfe to JS (70/2385/WI2, 70/3163/WI3). In the United Kingdom funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund).

Abbreviations

GBM
glioblastoma
GWA
genome-wide association study
SNP
single nucleotide polymorphism
WHO
World Health Organization
KPI
Karnofsky performance index
HR
hazard ratio
95%CI
95% confidence interval

Footnotes

Authors disclosures of potential conflicts of interests: The authors declare no conflict of interests.

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