Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (P<0.001) and are associated with oligodendroglial histology (P<0.001). Kaplan–Meier’s survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.
Diffuse gliomas, the most common primary malignant brain tumors, are classified by the World Health Organization (WHO) into astrocytoma, oligodendroglioma, and oligoastrocytoma based on histology and further graded into grade II to grade IV according to malignant features.1 Lower-grade gliomas, comprising grade II and grade III diffuse gliomas, exhibit an infiltrative nature and intrinsic tendency to recur or progress to higher-grade lesion ie grade IV glioblastoma. Although the current classification of lower-grade gliomas is based on histology and has prognostic implication, heterogeneous clinical outcomes exist among gliomas within each group. Such histology-based classification system also leads interobserver variability in diagnosis.2 Mounting evidence has suggested that biomarkers can aid tumor diagnosis, determine prognosis, and guide clinical management. Chromosome 1p and 19q codeletion, the genetic hallmark of oligodendrogliomas associated with long survival and chemo-radio sensitivity, represents the prototype molecular marker with unequivocal diagnostic, prognostic, and therapeutic utilities in diffuse gliomas.3, 4, 5, 6, 7 Isocitrate dehydrogenase (IDH) mutation is probably the most important molecular marker discovered in diffuse gliomas with breakthrough clinical values in the recent years.8 Apart from its use in difficult diagnostic situations,8, 9, 10 mutation of this enzyme also stratifies diffuse gliomas prognostically.11, 12 Recently, recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT), the gene encoding catalytic subunit of telomerase, were detected in ∼70% of malignant melanomas.13, 14 Mutations caused a cytosine-to-thymine transition at the positions of chr5, 1 295 228 (C228T) and 1 295 250 (C250T), and generated an identical 11 base-pair nucleotide sequence (5′-IndexTermCCCCTTCCGGG-3′) containing a consensus binding site (5′-IndexTermTTCC-3′) for E-twenty-six transcription factors.13, 14, 15 Importantly, this promoter mutation is associated with upregulation of TERT expression, suggesting it as a mechanism of telomerase activation in tumorigenesis.14, 16 Further studies demonstrated the high frequency of TERT promoter mutation in different histological types of diffuse gliomas, in particular oligodendrogliomas, oligoastrocytomas, and primary glioblastoma.16, 17, 18 Although TERT promoter mutation was shown to be associated with poor clinical outcome in glioblastoma patients,15, 18 clinical value of this newly identified mutation in lower-grade gliomas remains elusive. In this study, we conducted mutational analysis for TERT promoter in 237 lower-grade gliomas with the aim to examine the clinical value of TERT promoter mutation in terms of classification and prognostication in lower-grade gliomas.
Materials and methods
Patients and Tissue Samples
A total of 237 lower-grade gliomas diagnosed between 1990 and 2012 with formalin-fixed paraffin-embedded tissues available were retrieved from the tissue archive of the Department of Anatomical and Cellular Pathology, Prince of Wales Hospital (Hong Kong) and Department of Neurosurgery, Huashan hospital (Shanghai), comprising 105 diffuse astrocytomas (WHO grade II; AII), 63 anaplastic astrocytomas (WHO grade III; AAIII), 18 oligodendrogliomas (WHO grade II; OII), 3 anaplastic oligodendrogliomas (WHO grade III; AOIII), 45 oligoastrocytomas (WHO grade II; OAII), and 3 anaplastic oligoastrocytomas (WHO grade III; AOAIII). All cases were stained with haematoxylin & eosin and reviewed according to the 2007 WHO criteria.1 Clinical and survival data of the patients were retrieved from the respective institutional medical record systems. This study was approved by the Ethics Committee of Shanghai Huashan Hospital and the New Territories East Cluster-Chinese University of Hong Kong Ethics Committee.
Mutation Analysis of TERT Promoter and IDH1/IDH2
Tissues from representative tumor area with tumor content >70% were scrapped off from dewaxed sections and treated with proteinase K at a final concentration of 2 μg/μl in 10 mM Tris-HCl buffer (pH 8.5) at 55 °C for 2–18 h and then at 98 °C for 10 min. The crude cell lysate was centrifuged and supernatant was used for subsequent PCR analysis. The forward primer TERT-F (5′-IndexTermGTCCTGCCCCTTCACCTT-3′) and reverse primer TERT-R (5′-IndexTermCAGCGCTGCCTGAAACTC-3′) were used to amplify a 163 bp fragment spanning the two mutational hotspots (chr5, 1 295 228 (C228T) and 1 295 250 (C250T)) in TERT promoter region (Figure 1, Supplementary Figure S1 and S2). PCR was performed in 10 μl reaction mixture containing 1 μl of cell lysate, 0.3 mM of each dNTP, 2.5 mM MgCl2, 0.3 μM of each primer, and 0.2 U of KAPA HiFi HotStart DNA Polymerase (Kapa Biosystems Wilmington, DE, USA), and was initiated at 95 °C for 5 min, followed by 40–45 cycles of 98 °C for 20 s, 68 °C for 15 s and 72 °C for 30 s, and a final extension of 72 °C for 1 min. Products were then treated with exonuclease I and alkaline phosphatase (TakaRa, Japan). Sequencing was performed using BigDye Terminator Cycle Sequencing kit v1.1 (Life Technologies). The products were resolved in Genetic Analyzer 3130xl and analyzed by Sequencing Analysis software. Mutational hotspots of IDH1 at R132 and IDH2 at R172 were evaluated by direct sequencing as previously described.19
Chromosome 1p/19q Status by Fluorescence in situ Hybridization
Chromosome 1p/19q status was evaluated by fluorescence in situ hybridization as reported previously.20 In brief, 5-μm thick formalin-fixed, paraffin-embedded sections were deparaffinized in xylene, treated with 1 M sodium thiocyanate at 80 °C for 10 min, digested in pepsin solution at 37 °C for 20–30 min, rinsed in milli-Q water and dehydrated. Locus-specific probes were generated from bacterial artificial chromosome clones using nick translation, in the presence of Spectrum Orange deoxyuridine triphosphate (dUTP) or Spectrum Green dUTP. The labeled probes were mixed with Cot-1 DNA (Life Technologies) in Hybrisol VI solution (Appligene Oncor, Graffenstaden, France), applied to the section and denatured. Hybridization was carried out at 37 °C overnight for 16 h. Sections were washed in 1.5 M urea in 0.1 × saline sodium citrate at 48 °C for 30 min and then in 2 × saline sodium citrate at 48 °C for 5 min. After washing, sections were stained with Vectashield mounting medium containing 4′,6-diamidino-2-phenylindole (Vector Laboratories) and viewed under a Zeiss Axioplan fluorescence microscope (Carl Zeiss Microscopy LLC, NY, USA). Hybridizing signals in at least 100 non-overlapping nuclei were counted. The loci interrogated were 1p36.3 (RP11-62M23 labeled red)/1q25.3-q31.1 (RP11-162L13 labeled green) and 19q13.3 (CTD-2571L23 labeled red)/19p12 (RP11-420K14 labeled green). A sample was considered 1p or 19q deleted when >50% of counted nuclei exhibited one target (red) signal and two reference (green) signals.
Statistical analysis was performed using IBM SPSS Statistics 20 (IBM Corporation, NY, USA). Correlation between molecular markers and clinical parameters were examined by χ2-test or Fisher’s exact test, whichever was appropriate. Comparison between two groups was performed by Student’s t-test or Mann–Whitney U-test. Comparison between three or more groups used one-way analysis of variance (ANOVA) and post hoc analysis with Bonferroni correction. Overall survival (OS) was defined as the time between diagnosis and death or last follow-up. Progression-free survival (PFS) was defined as the time between diagnosis and tumor recurrence or progression. Survival curves were plotted by Kaplan–Meier method and analyzed by Log-rank test. Multivariate analysis was performed by Cox proportional hazards model. P-value of <0.05 (two sided) was considered statistically significant.
The male to female ratio of the cohort was 1:0.63. The mean and median age of the patients were 40.5 years and 40 years (range 3–9), respectively. There were 15 pediatric patients (at or below 18 years) (five diffuse astrocytomas, five anaplastic astrocytomas, one oligodendroglioma and four oligoastrocytomas) in the cohort. Among the 224 cases with known tumor location, 89 (40%), 49 (22%), 25 (11%), and 3 (1%) tumors located in frontal, temporal, parietal, and occipital lobe, respectively. Twelve (5%) cases involved infratentorial region, 24 (11%) cases involved more than one lobe and 22 (10%) cases involved other regions including corpus callosum, thalamus, and basal ganglia. Treatment data in operation, radiotherapy, and chemotherapy was available in 214 of 237 (90%), 201 of 237 (85%), and 200 of 237 (84%) patients, respectively. In total,123 of 214 (58%) patients received total resection, 145 of 201 (72%) patients received radiotherapy and 114 of 200 (57%) patients received chemotherapy. In total, 101 of 200 (51%) patients received concomitant chemo-radiotherapy.
TERT Promoter Mutation
Mutation in TERT promoter was found in 67 of 237 (28%) lower-grade gliomas examined, including 16 of 105 (15%) diffuse astrocytomas, 16 of 63 (25%) anaplastic astrocytomas, 13 of 18 (72%) oligodendrogliomas, 3 of 3 (100%) anaplastic oligodendrogliomas, 17 of 45 (38%) oligoastrocytomas and, 2 of 3 (67%) anaplastic oligoastrocytomas. Two pediatric astrocytomas (one diffuse astrocytoma and one anaplastic astrocytoma) harbored TERT promoter mutation. Among the 67 mutated tumors, C228T and C250T mutations were mutually exclusive and were observed in 44 (19%) cases (12/105 diffuse astrocytomas, 12/63 anaplastic astrocytomas, 7/18 oligodendrogliomas, 2/3 anaplastic oligodendrogliomas, 10/45 oligoastrocytomas and 1/3 anaplastic oligoastrocytomas) and 23 (10%) cases (4/105 diffuse astrocytomas, 4/63 anaplastic astrocytomas, 6/18 oligodendrogliomas, 1/3 anaplastic oligodendrogliomas, 7/45 oligoastrocytomas and 1/3 anaplastic oligoastrocytomas), respectively (Table 1, Figure 2a and Supplementary Figure S2).
Correlating TERT promoter mutation with clinicopathological variables, patients with TERT promoter mutation were older than those without the mutation (mean age 44.3 vs 39, P=0.007). No association was observed between TERT promoter mutation and gender. Tumors with oligodendroglial histology showed high frequency of TERT promoter mutation (16/21, 76%) compared with tumors with mixed oligoastrocytic histology (19/48, 40%) and tumors with astrocytic histology (32/168, 19%) (P<0.001) (Figure 2b).
Forty-nine of 67 (73%) TERT-mutated tumors harbored IDH mutation and 109 of 170 (64%) TERT wild-type tumors had IDH mutation (Figure 2c). Among the IDH-mutated tumors, TERT promoter mutation was found in 14/98 (14%), 16/20 (80%), and 19/40 (48%) gliomas with astrocytic, oligodendroglial, and oligoastrocytic histology, respectively (P<0.001). Among tumors with wild-type IDH, TERT promoter mutation was detected in 18/70 (22%) gliomas with astrocytic histology exclusively (6 diffuse astrocytomas and 12 anaplastic astrocytomas). Wild-type TERT was found in 52/70 (74%), 1/1, and 8/8 tumors with astrocytic, oligodendroglial, and oligoastrocytic histology, respectively. Opposite correlations between IDH mutation and TERT promoter mutation were observed in subsets of astrocytic tumors with intact 1p/19q and oligodendroglial tumors. Among the astrocytic tumors with intact 1p/19q, 9 of 27 (33%) TERT-mutated tumors harbored IDH mutation and 80 of 131 (61%) TERT wild-type tumors had IDH mutation (P=0.008) (Figure 2d). In contrast, among the subsets of oligodendroglial tumors, all 35 TERT-mutated tumors harbored IDH mutation and 25 of 34 (74%) TERT wild-type tumors had IDH mutation (P=0.001) (Figure 2e). Notably, Patients with IDH wild-type-TERT-mutated tumors were older (mean age=51 years) than those with IDH wild-type-TERT wild-type tumors (mean age=36.3 years, P<0.001), IDH-mutated-TERT wild-type tumors (mean age=40.6 years, P=0.012) and trended to be older than IDH-mutated-TERT-mutated tumors (mean age=41.8 years, P=0.068) (Figure 2g).
Chromosome 1p/19q codeletion was detected in 28 of 65 (43%) TERT-mutated tumors and 9 of 167 (5%) TERT wild-type tumors (P<0.001) (Figure 2f). Among the 1p/19q codeleted tumors, TERT promoter mutation was identified in 5/7 (71%) gliomas with astrocytic histology, 10/12 (83%) gliomas with oligodendroglial histology, and 13/18 (72%) gliomas with oligoastrocytic histology. Among tumors lacking 1p/19q codeletion, 27/158 (17%) gliomas with astrocytic histology, 5/8 (63%) gliomas with oligodendroglial histology and 5/29 (17%) gliomas with oligoastrocytic histology harbored TERT promoter mutation (P=0.006).
Chromosome 1p/19q codeletion was detected in 37/232 (16%) cases including 7/102 (7%) diffuse astrocytomas, 10/17 (59%) oligodendrogliomas, 2/3 (67%) anaplastic oligodendrogliomas, and 18/44 (41%) oligoastrocytomas (Table 1, Figure 2a). Five cases (three diffuse astrocytomas, one oligodendroglioma and one oligoastrocytoma) were not examined for 1p/19q FISH owing to the lack of tissue section. None of the 15 pediatric gliomas had 1p/19q codeletion. All 37 1p/19q codeleted tumors harbored IDH mutation and 117/195 (60%) tumors lacking 1p/19q codeletion harbored IDH mutation (P<0.001).
IDH mutation was found in 71/105 (68%) diffuse astrocytomas, 27/63 (43%) anaplastic astrocytomas, 17/18 (94%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 37/45 (82%) oligoastrocytomas, and 3/3 (100%) anaplastic oligoastrocytomas, with an overall mutation frequency of 67% (158/237) (Table 1, Figure 2a). In the 158 IDH-mutated gliomas, 151 tumors harbored IDH1 mutation and 7 tumors harbored IDH2 mutation. One 18-year-old patient with anaplastic astrocytoma had mutation in IDH1.
Follow-up data were available in 231 patients. The median follow-up, median PFS and median OS of the cohort were 113 months, 56 months, and 83.2 months, respectively.
Univariate analysis showed age ≤35 years (P=0.02), WHO grade II (P<0.001), oligodendroglial histology (P=0.006), IDH mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with longer PFS. Age ≤35 years (P=0.005), WHO grade II (P<0.001), oligodendroglial histology (P<0.001), TERT promoter mutation (P=0.037), IDH mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with longer OS (Table 2, Figure 3a–f). Prognostic value of TERT promoter mutation was further evaluated in subset analysis (Table 3, Figure 3g–r). Among the 157 IDH-mutated lower-grade gliomas, 49 TERT promoter-mutated tumors showed longer progression-free survival (P=0.001) and longer OS (P<0.001). As TERT promoter mutation was highly associated with 1p/19q codeletion, which may account for the favorable prognostic effect, we evaluated the subset of 116 IDH-mutated tumors lacking 1p/19q codeletion and found that 19 TERT promoter-mutated tumors exhibited favorable PFS (P=0.027) and OS (P=0.004). Consistent with this observation, subset analysis in 97 IDH-mutated astrocytomas also revealed that TERT promoter mutation in 14 astrocytomas was associated with good prognosis in both PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). In the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated astrocytomas exhibited unfavorable PFS (P=0.007) and OS (P=0.008).
Multivariate analysis was performed by Cox proportional hazards model to evaluate the independent prognostic values of the clinical and molecular variables (Table 4). Variables evaluated in multivariate analysis included age, WHO grade, tumor histology, TERT promoter mutation, IDH mutation, and 1p/19q codeletion. Age≤35 years (P=0.001), WHO grade II (P<0.001), IDH mutation (P=0.013) and 1p/19q codeletion (P=0.036) were favorable prognostic factors for PFS. Age≤35 years (P=0.001), WHO grade II (P<0.001), and IDH mutation (P=0.009) were favorable prognostic factors for OS. 1p/19q codeletion showed a strong trend as good prognostic factor for OS (P=0.067). As TERT promoter mutation showed opposite prognostic value in IDH-mutated and IDH wild-type tumors in univariate analysis, multivariate analysis was conducted separately in the two subsets to further define the prognostic implication of TERT promoter mutation. Among IDH-mutated tumors, Age≤35 years (P=0.015), WHO grade II (P=0.001), TERT promoter mutation (P=0.007), and 1p/19q codeletion (P=0.047) were favorable prognostic factors for PFS. Age≤35 years (P=0.013), WHO grade II (P<0.001), and TERT promoter mutation (P=0.002) were good prognostic factors for OS. 1p/19q codeletion showed a strong trend as good prognostic factor for OS (P=0.057). Among IDH wild-type tumors, WHO grade II was a favorable prognostic factor for PFS (P=0.002) and OS (P<0.001). TERT promoter mutation exhibited as a poor prognostic factor for PFS (P=0.027) and a trend as a poor prognostic factor for OS (P=0.07).
Our study evaluated the frequency of TERT promoter mutation and its clinical significance in lower-grade gliomas. We demonstrated that TERT promoter mutation was frequently detected in lower-grade gliomas, particularly in oligodendroglial tumors. The strong association of TERT promoter mutation with oligodendroglial histology and 1p/19q codeletion suggested that this activating mutation was involved in oligodendroglial oncogenesis, which was also demonstrated by other groups.15, 16, 17 Koelsche et al17 analyzed over 1500 tumors of nervous system and found that TERT promoter mutation was inversely associated with IDH mutation. Similar inverse correlation was shown by Nonoguchi et al18 examining over 350 glioblastomas. In our cohort of lower-grade gliomas, no correlation was found between IDH mutation and TERT promoter mutation. Interestingly, we observed opposite correlations between the two molecular markers in different subsets of tumors—inverse correlation in the subset of astrocytomas with intact 1p/19q and co-occurring correlation in the subset of oligodendroglial tumors. These observations were consistent with the current literature15, 16, 17, 18 and we speculated that the co-occurring association between 1p/19q codeletion and IDH mutation as well as 1p/19q codeletion and TERT mutation ‘neutralized’ the inverse correlation between IDH mutation and TERT mutation in the whole cohort. Nevertheless, IDH mutation and 1p/19q codeletion have been suggested as early event in gliomagenesis.21, 22 With the high frequency of TERT promoter mutation identified in oligodendrogliomas and its co-occurrence with 1p/19q codeletion, it will be interesting to examine these molecular markers in paired primary and recurrent oligodendrogliomas to determine their temporal relationship.
Apart from the subgroup of lower-grade gliomas harboring all the three genetic alterations, there existed TERT promoter-mutated lower-grade gliomas lacking 1p/19q codeletion and IDH mutation. Importantly, prognostic difference was found between these molecular subgroups. TERT promoter mutation had opposite prognostic values in IDH-mutated and IDH wild-type tumors in both univariate analysis and multivariate analysis. In IDH wild-type lower-grade gliomas, TERT promoter mutation identified aggressive tumors. TERT promoter mutation was frequently detected in primary glioblastoma lacking IDH mutation and was associated with poor prognosis in glioblastoma patients.15, 17 The IDH wild-type-TERT-mutated lower-grade gliomas identified in our series, with a similarly worsened outcome compared with the IDH-mutated lower-grade gliomas, may require more treatment and follow-up. In contrast, among IDH-mutated lower-grade gliomas, particularly in astrocytomas, TERT promoter mutation exhibited favorable prognosis. Existence of this good prognostic subgroup in IDH-mutated lower-grade gliomas was further evidenced by the association between TERT promoter mutation and good prognosis in IDH-mutated tumors lacking 1p/19q codeletion as 1p/19q codeletion is a group with good prognosis anyway. These findings suggested that TERT promoter mutation could potentially aid the molecular stratification of lower-grade gliomas in addition to IDH mutation and 1p/19q codeletion, especially in patients with astrocytic tumors.
Contrary to the concept of promoter methylation leading to gene silencing, TERT promoter methylation was found to be associated with TERT expression in other cancers including pediatric brain tumors.23, 24, 25 Together with the exceedingly low frequency of TERT promoter mutation identified in over 350 pediatric brain tumors by Koelsche et al,17 TERT promoter methylation probably represents a major mechanism for telomerase activation in pediatric brain tumors. Intriguingly, a recent study by Arita et al26 demonstrated that TERT promoter mutation rather than methylation was the main mechanism for TERT upregulation in adult gliomas. Such results not only illustrated the diverse mechanisms of telomerase activation in different cancer types, but also demonstrated the distinct pathogenesis between pediatric and adult brain tumors.
One of the crucial findings in this study was the opposite prognostic values of TERT promoter mutation in IDH-mutated and IDH wild-type lower-grade gliomas. Interestingly, subgroup-specific prognostic implication of TERT promoter mutation was also demonstrated in medulloblastoma by Remke et al27, with the mutation identified patients with good prognosis in SHH subgroup and patients with bad prognosis in Group 4 subgroup. Such subgroup-specific prognostic values, together with its high frequency in certain groups of brain tumors and the relatively easy assay method (PCR followed by direct sequencing), made TERT promoter mutation as an emerging molecular marker for patient stratification in neuro-oncology.
In conclusion, TERT promoter is frequently mutated in lower-grade gliomas, with a particularly high incidence in oligodendroglial tumors. The mutations identify a favorable prognostic subset of IDH-mutated-1p/19q intact or astrocytic tumors and an aggressive subset of IDH wild-type tumors. Our study suggests the potential values of TERT promoter mutational analysis in molecular classification and prognostic evaluation in lower-grade gliomas in the era of personalized medicine.
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This study was supported by the National Science Foundation of China (grant no. 81172412).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Modern Pathology website
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