TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
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Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
KeywordsTERT promoter mutations SHH pathway Adult Medulloblastoma
Medulloblastoma is a highly malignant embryonal brain tumor located in the posterior fossa [6, 29, 33, 35]. While this tumor comprises the most common malignant brain tumor in children, it only accounts for approximately 1 % of primary CNS tumors in adults [18, 20]. The current consensus recognizes four core molecular subgroups (WNT, SHH, Group 3, and Group 4) with distinct molecular, demographic, clinicopathological, and prognostic characteristics [5, 15, 16, 26, 27, 37, 38, 41, 42]. The defining features of medulloblastoma subgroups differ dramatically according to age at diagnosis [15, 27, 41]. Specifically, Group 3 tumors are largely confined to non-adults, SHH tumors are most frequent in infants and adults, while WNT and Group 4 medulloblastomas are mostly observed in pediatric cohorts [15, 24, 27, 38, 41]. Particularly within SHH tumors, age-associated heterogeneity was observed regarding the transcriptional characteristics, somatic copy number alterations (SCNA), and the prognostic implications of biomarkers [15, 18, 38, 40]. Delineation of tumorigenic features characteristic for these age-related differences, particularly within SHH tumors, are highly desirable to understand these clear biological and prognostic discrepancies.
Telomere maintenance is fundamentally important to normal self-renewing stem cells and cancer cells [3, 7, 9, 14, 22]. It has been suggested that tumors derived from cell populations with low self-renewal capacity generally rely on alterations that restore telomerase activity, while epigenetic mechanisms maintain telomerase activity in tumor types derived from self-renewing stem cells . The identification of recurrent telomerase reverse transcriptase (TERT) promoter mutations in 21 % of 91 medulloblastomas  is intriguing, since other mechanisms converging on increased telomerase activity including alternative lengthening of telomeres (ALT)  or mutations affecting the ATRX/DAXX complex are excessively uncommon in medulloblastoma [12, 25, 32, 34, 39]. Although TERT mutations have been reported in several cancers [2, 10, 11, 13, 19, 43], their putative association with distinct biological behavior and clinical or even prognostic characteristics has not been comprehensively studied. The initial analyses of TERT mutations in medulloblastoma  mainly catalogued the mutational frequency rather than correlating the molecular and clinical features of these mutations in a subgroup-specific manner.
In this study, we analyzed a representative set of 466 medulloblastomas for TERT promoter mutations. Subsequently, we correlated the mutational distribution with clinicopathological features, outcome, and molecular characteristics in a subgroup-specific manner. We demonstrate that TERT promoter mutations comprise the most recurrent mutation in adult SHH tumors identified to date and potentially define distinct prognostic subgroups in SHH and Group 4 medulloblastoma patients.
Materials and methods
Tumor material and patient characteristics
Clinicopathological and molecular characteristics according to TERT mutational status
Gene expression and copy number analysis
Subgroup affiliation was determined using nanoString limited gene expression profiling as previously described . Somatic copy number alterations were assessed on the Affymetrix Single Nucleotide Polymorphism (SNP) 6.0 array platform in 418 of 466 cases to identify SCNAs specific for TERT mutant and wild-type tumors. Raw copy number estimates were obtained in dChip, followed by CBS segmentation in R as previously described . Somatic copy number alterations were identified using GISTIC2 . TERT expression levels were compared using R2 (www.r2.amc.nl). Differences in expression were tested using one-way ANOVA.
Isolated DNA (25 ng) from all 466 tumors and 7 matched germline samples (25 ng) was amplified by PCR. PCRs contained 1 μl DNA template, 10 μM forward (5′-CAG GGC ACG CAC ACC AG-3′) and reverse (5′-GTC CTG CCC CTT CAC CTT C-3′) TERT-specific primers, and 12.5 μl HotStar Taq Plus Master Mix (Qiagen, Gaithersburg, Maryland, USA) in a 25 μl total reaction volume. Cycle parameters comprised 95 °C × 15 min; 28 cycles of 98 °C × 40 s, 65 °C × 30 s, 72 °C × 1 min; 72 °C × 10 min. PCRs were carried out using the C1000 Thermal Cycler (BioRad, Hercules, CA, USA). PCR products were purified with the PureLink PCR Micro kit (Life Technologies, Burlington, ON, Canada). In all experiments, controls were included in the absence of DNA to rule out contamination by PCR products. Templates for Sanger sequencing were analyzed with forward (5′-CAG CGC TGC CTG AAA CTC-3′) and reverse (5′-GTC CTG CCC CTT CAC CTT C-3′) sequencing primers using dGTP BigDye Terminator v3.0 Cycle Sequencing Ready Reaction Kit (Life Technologies), and 5 % DMSO on the ABI3730XL capillary genetic analyzer (Life Technologies).
Two primers (forward primer, 5′-CAG CGC TGC CTG AAA CTC-3′; reverse primer, 5′-GTC CTG CCC CTT CAC CTT C-3′) were designed to amplify a 163-bp product encompassing C228T and C250T hotspot mutations in the TERT promoter—corresponding to the positions 124 and 146 bp, respectively, upstream of the ATG start site. Two fluorogenic LNA probes were designed with different fluorescent dyes to allow single-tube genotyping. One probe was targeted to the WT sequence (TERT WT, 5′-5HEX-CCC CTC CCG G-3IABkFQ-3′), and one was targeted to either of the two mutations (TERT mut, 5′-56FAM-CCC CTT CCG G-3IABkFQ). Primer and probes were custom designed by Integrated DNA Technologies (Coralville, Iowa, USA) using internal SNP design software, and sequence homogeneity was confirmed by comparison to all available sequences on the GenBank database using BLAST (http://www.ncbi.nlm.nih.gov/BLAST/). Primers were optimized to avoid for hairpins and homo- and heterodimers. Primers and probes were obtained from Integrated DNA Technologies.
Real-time PCR was performed in 25 μl reaction mixtures containing 12.5 μl of TaqMan Universal Master Mix II with UNG (Applied Biosystems), 900 nM concentrations of each primer, 250 nM TERT WT probe, 250 nM TERT MUT probe, and 1 μl (25 ng) of sample DNA. Thermocycling was performed on the StepOnePlus (Applied Biosystems) and consisted of 2 min at 50 °C, 10 min at 95 °C, and 40 cycles of 95 °C for 15 s and 60 °C for 1 min.
Analysis was performed using StepOne Software, version 2.1. Samples were considered mutant if they had CT values of ≤39 cycles. Each sample was verified visually by examining the PCR curves generated to eliminate false positives due to aberrant light emission. End-point allelic discrimination genotyping was performed by visually inspecting a plot of the fluorescence from the WT probe versus the MUT probe generated from the post-PCR fluorescence read.
Survival time according to TERT mutational status was assessed using the Kaplan–Meier estimate and a log-rank test. Comparisons of binary and categorical patient characteristics between subgroups and cohorts were performed using the two-sided Fisher’s exact test or Chi-squared test. Continuous variables were analyzed using the Mann–Whitney U test. p values <0.05 were considered statistically significant. Multivariate Cox proportional hazards regression was used to adjust for additional covariates using the survival R package (v.2.36). All other statistical analyses were performed using StataSE 12 (Stata Corp. College Station, TX, USA) and Graphpad Prism 5 (La Jolla, CA, USA).
Characteristics of TERT-mutated medulloblastomas
TERT mutations are specifically enriched in SHH medulloblastomas
Clinicopathological and molecular characteristics of SHH medulloblastoma according to TERT mutational status
Prognostic implications of TERT mutations
Survival analysis restricted to specific age groups
Distinct somatic copy number alterations of TERT-mutated medulloblastomas
The underlying biology of adult medulloblastomas remains poorly understood. Next-generation sequencing studies have revealed a broad spectrum of novel, potentially tumorigenic mutations in the recent past, but none of these studies focused on adult medulloblastomas [12, 25, 32, 34, 39]. In addition, the vast majority of these mutations are not recurrent enough to stratify patients into distinct clinical and prognostic subgroups.
In this study, we demonstrate that TERT promoter mutations, initially described in melanoma [10, 11], comprise the most recurrent mutation described so far across medulloblastoma subgroups, with a particular enrichment in older patient cohorts. These somatic mutations are especially common in older patients with SHH tumors (83 %) and to a lesser extent in adults with WNT medulloblastomas (11 %). Based on the transcriptional heterogeneity of SHH tumors in infant and adult patients, we suspect that the adult cluster mainly comprised TERT-mutated medulloblastomas . According to the initial classification of tumor types with TERT mutations at frequencies over 15 % (TERT-high) vs. below this threshold (TERT-low) , our report suggests distinct baseline telomerase activity of the cell of origin in each of the subgroups (Group 3 ≥ Group 4 > WNT >> SHH). Furthermore, the identification of recurrent TERT promoter mutations makes a compelling argument that the increasing availability of whole-genome sequencing results may substantially add to a refined understanding of the mutational landscape of different biological and age-driven medulloblastoma subgroups, since earlier next-generation sequencing studies focusing on the protein-coding regions had not encompassed gene-regulatory regions including promoter mutations.
In this study, we demonstrate that the mutational status of the TERT promoter can segregate individuals with SHH and Group 4 medulloblastomas with distinct prognostic outcomes, while a prognostic impact of this mutation was not observed in glioblastomas . Molecular mechanisms converging on TERT up-regulation were recently reported to be associated with dismal prognosis in pediatric brain cancers . Our findings in Group 4 tumors with TERT mutations follow this pattern, while SHH tumors with TERT mutations comprise a prognostically favorable subgroup. Notably, survival curves of SHH tumors increasingly approximate with extended follow-up. We hypothesize that this pattern might be due to secondary malignancies and late relapses in older SHH tumors [36, 37, 38]. Since virtually all of the TERT promoter mutations encompass the mutational hotspots C228T and C250T, patient stratification can be carried out using a single PCR followed up with Sanger sequencing or with a single experiment using our newly designed Taqman-based genotyping assay. The latter assay is particularly suitable for routine clinical applications as it is highly sensitive and specific (5 ng DNA input is sufficient). Furthermore, our Taqman-based genotyping assay can be used on DNA derived from fresh-frozen and formalin-fixed paraffin-embedded tissue, since it only amplifies a short DNA fragment.
Both hotspot mutations C228T and C250T create an E-twenty-six (ETS) binding motif [10, 11] resulting in up-regulation of TERT expression at the mRNA level , which was not observed at the protein level in glioblastomas . We now demonstrate that SHH tumors with TERT mutations are mostly mutually exclusive with those harboring 10q loss (p = 0.017) Notably, the relatively favorable prognosis of TERT-mutated SHH medulloblastomas may be explained by the relative lack of high-risk biomarkers [17, 18, 24, 44].
In summary, we describe the demographic, clinicopathological, and biological implications of TERT promoter mutations in a subgroup-specific fashion. This study underlines the dependence of adult WNT and SHH tumors to reacquire telomerase activity and suggests a potential prognostic utility of TERT mutational analysis in an era of individualized therapy.
We thank Susan Archer for technical writing, and Nick Downey from Integrated DNA Technologies for support with probe/primer design. We acknowledge CRB HCL—Neurobiotec tumor bank (Hospices Civils de Lyon, Lyon, France). MDT is supported by a CIHR Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and the University of Toronto, and operating funds from the Canadian Institutes of Health Research, the National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation. MR is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/German Cancer Aid and funds from the Baden-Wurttemberg Foundation. VR is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. KZ acknowledges research support from MH CZ-DRO FNBr 65269705. AK was supported by the TAMOP-4.2.2A-11/1/KONV-2012-0025 project and the János Bolyai Scholarship of the Hungarian Academy of Sciences.
Conflict of interest
The authors declare no conflicts of interest.
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