Cynthia Hawkins

University of Toronto, Toronto, Ontario, Canada

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Publications (153)1080.79 Total impact

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    ABSTRACT: Astrocytic inclusions (AIs) have been identified on histologic specimens of patients with early onset seizures, and the proteomic contents have been described. The aim of this study was to compare the clinical, electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance imaging (MRI), and surgical outcomes of AIs relative to focal cortical dysplasia (FCD).
    Epilepsia 08/2014; · 3.96 Impact Factor
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    ABSTRACT: Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors.
    Cancer Discovery 08/2014; · 10.14 Impact Factor
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    ABSTRACT: Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.
    Acta Neuropathologica 08/2014; · 9.73 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II–IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III–IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II–IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.
    Acta Neuropathologica 07/2014; · 9.73 Impact Factor
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    ABSTRACT: Gliomas are a deadly group of childhood and adult cancers associated with high relapse rate following current therapies. Limitless self-renewal is a hallmark of cancer recurrence and is controlled by telomerase activation and telomere maintenance. We have recently uncovered THOR (TERT Hypermethylated Oncological Region) which is paradoxically hypermethylated in gliomas with telomerase activation. In order to further explore the biological impact of THOR hypermethylation on self renewal and telomere maintenance of gliomas we undertook a stepwise approach.
    Neuro-oncology. 07/2014; 16 Suppl 3:iii30.
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with no effective therapy and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. This data is critical for the development of better therapies for these children.
    Neuro-oncology. 07/2014; 16 Suppl 3:iii26-iii27.
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    ABSTRACT: Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, The Netherlands, under the sponsorship of the International Society for Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present “white paper” catalogues the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN-Haarlem” guidelines. Salient recommendations include that: 1) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; 2) diagnoses should be “layered” with histologic classification, WHO grade, and molecular information listed below an “integrated diagnosis”; 3) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; 4) some pediatric entities should be separated from their adult counterparts; 5) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology and 6) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the 4th Edition of the WHO classification of central nervous system tumors.
    Brain Pathology 07/2014; · 4.74 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
    Nature Genetics 04/2014; · 35.21 Impact Factor
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    ABSTRACT: Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P = 0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P = 0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P = 0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P = 0.02), however is no longer significant when controlling for subgroup (P = 0.07). The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 02/2014; · 2.35 Impact Factor
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    ABSTRACT: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
    Nature 02/2014; · 38.60 Impact Factor
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    ABSTRACT: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Journal of Clinical Oncology 02/2014; · 18.04 Impact Factor
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    ABSTRACT: We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.
    Nature Reviews Cancer 01/2014; 14(2):92-107. · 29.54 Impact Factor
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    ABSTRACT: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.
    European journal of cancer (Oxford, England: 1990) 01/2014; · 4.12 Impact Factor
  • Patricia Rakopoulos, Cynthia Hawkins
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    ABSTRACT: Paediatric high grade astrocytomas (HGA) are diffusely infiltrative and highly aggressive brain tumours that account for nearly 20% of all central nervous system tumours in children. They are classified as anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV). Grade IV HGAs that are centred in the pons and diffusely involve the brainstem are referred to as Diffuse Intrinsic Pontine Gliomas (DIPGs). This chapter describes some of the most common genetic alterations identified in paediatric HGAs, and focuses on recent findings which underscore the major differences between adult and paediatric HGAs as well as the significance of epigenetic dysregulation during tumourigenesis. The diagnostic and prognostic utility of screening for various genetic alterations is also discussed.
    Diagnostic Histopathology. 01/2014;
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    ABSTRACT: Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
    Acta Neuropathol. 01/2014;
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    Diana Marcela Muñoz, Cynthia Hawkins
    Cell cycle (Georgetown, Tex.) 12/2013; 13(3). · 5.24 Impact Factor
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    ABSTRACT: Background Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems.Methods We have established a first cell line, BT183, from a case of ETMR and characterized its molecular and cellular features. LIN28 knockdown was performed in BT183 to examine the potential role of Lin28 in regulating signaling pathway gene expression in ETMR. Cell line findings were corroborated with immunohistochemical studies in ETMR tissues. A drug screen of 73 compounds was performed to identify potential therapeutic targets.ResultsThe BT183 line maintains C19MC amplification, expresses C19MC-encoded microRNAs, and is tumor initiating. ETMRs, including BT183, have high LIN28 expression and low let-7 miRNA expression, and show evidence of mTOR pathway activation. LIN28 knockdown increases let-7 expression and decreases expression of IGF/PI3K/mTOR pathway components. Pharmacologic inhibition of the mTOR pathway reduces BT183 cell viability.ConclusionsBT183 retains key genetic and histologic features of ETMR. In ETMR, Lin28 is not only a diagnostic marker but also a regulator of genes involved in growth and metabolism. Our findings indicate that inhibitors of the IGF/PI3K/mTOR pathway may be promising novel therapies for these fatal embryonal tumors. As the first patient-derived cell line of these rare tumors, BT183 is an important, unique reagent for investigating ETMR biology and therapeutics.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Diencephalic syndrome (DS) is a clinical disorder of metabolism associated with poor outcome in children with low-grade gliomas (LGGs). Since survival has been primarily reported with aggressive therapy, we report outcome data for these patients using a current, contrasting chemotherapy-driven approach. We performed a population-based review of DS patients treated with chemotherapy from 1997-2012. Metabolic rate was assessed in selected cases using open-circuit calorimetry to generate resting energy expenditure (REE) data. Tumor tissue was analyzed for BRAF alterations. Survival was compared with an age-related, radiotherapy naïve cohort of non-DS children with location-matched LGGs. Nine children (1.7 % of 520 LGG diagnoses) fulfilled DS criteria. The median diagnostic age was 1.49 years (0.55-2.69 years), although neurofibromatosis Type-I patients were older (p = 0.005). All tumors analyzed exhibited either NF1 mutation or BRAF fusion. Seven tumors were histologically confirmed as low grade astrocytomas, one demonstrated neurocytic features, and one NF1 case was diagnosed using imaging and clinical criteria. All patients received chemotherapy, with seven cases also receiving initial nutritional supplementation. All nine gained weight after only 6 months of treatment. Two DS patients had serial REE measurements, revealing a hypermetabolic state (over 200 % of predicted REE) at diagnosis which reduced to normal range with therapy. First-line chemotherapy treatment resulted in one minor response, stable disease in four cases, with progression in the remaining four patients. Although DS patients demonstrated inferior initial progression-free survival when compared to non-DS counterparts (5 years: 22 versus 60 %, p = 0.015), all DS children remain alive at a median follow up of 5.3 years (1.2-14.9 years) with none requiring radiotherapy. Long-term sequelae included pituitary and visual dysfunction, learning difficulties and paradoxical, inappropriate weight gain. DS can be managed with non-aggressive chemotherapeutic, radiation-sparing strategies supplemented by temporary nutritional support. Multiple lines of therapy may be required to overcome disease progression but excellent survival and metabolic outcomes can be achieved. Continued surveillance is mandatory to prevent significant weight gain and support affected children with clinical sequelae.
    Journal of Neuro-Oncology 11/2013; · 3.12 Impact Factor
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    ABSTRACT: 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.
    Acta Neuropathologica 10/2013; · 9.73 Impact Factor
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    ABSTRACT: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.
    The Lancet Oncology 10/2013; · 25.12 Impact Factor

Publication Stats

7k Citations
1,080.79 Total Impact Points

Institutions

  • 2004–2014
    • University of Toronto
      • • Department of Paediatrics
      • • Hospital for Sick Children
      • • Division of Neurology
      Toronto, Ontario, Canada
  • 2003–2014
    • SickKids
      • • Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC)
      • • Division of Hematology/Oncology
      • • Division of Pathology
      • • Division of Neurosurgery
      Toronto, Ontario, Canada
  • 2012
    • McGill University
      • Department of Human Genetics
      Montréal, Quebec, Canada
  • 2011
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2009
    • McMaster University
      • Division of Hematology/Oncology
      Hamilton, Ontario, Canada
  • 2008
    • University of Alberta
      • Department of Pediatrics
      Edmonton, Alberta, Canada
    • Taipei Veterans General Hospital
      • General Neurosurgery Division
      T’ai-pei, Taipei, Taiwan