Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Abstract: Ependymoma is a malignant pediatric brain tumor, often incurable under the current treatment regimen. We aimed to evaluate the expression of microRNAs (miRs) in pediatric ependymoma tumors in an attempt to identify prognostic molecular markers which would lead to potential therapeutic targets. Following miR-array expression analysis, we focused on 9 miRs that correlated with relapse which were further validated by quantitative real-time PCR (qRT-PCR) in a cohort of 67 patients. Western blotting and immunohistochemistry were used to measure target protein expression in 20 and 34 tumor samples, respectively. High expression of miR-124-3p significantly correlated with the lower progression-free survival (PFS) of 16% compared to 67% in those expressing low levels (P = .002). Interestingly, in the group of patients with local disease (n = 56) expression levels of this miR distinguished 2 subgroups with a significantly different outcome (P = .001). miR-124-3p was identified as an independent prognostic factor of relapse in the multivariate analysis performed in the whole cohort and in the group with localized disease. In the localized group, a patient expressing high levels of miR-124-3p had a 4.1-fold increased risk for relapse (P = .005). We demonstrated the direct binding of miR-124-3p to its target TP53INP1. Negative TP53INP1 protein levels correlated with a poor outcome (P = .034). We propose miR-124-3p and TP53INP1 as new biomarkers for prognostic stratification that may be possible therapeutic targets for ependymoma.
    Type of Publication: Journal article published
    PubMed ID: 28437838
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
  • 3
    Keywords: DISTINCT ; GENE ; BREAST-CANCER ; COPY-NUMBER ; SONIC HEDGEHOG ; GERMLINE ; LI-FRAUMENI-SYNDROME ; ACUTE MYELOID-LEUKEMIA ; telomere length ; FAMILIAL SYNDROME
    Abstract: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acutemyeloid leukemia. These findings connect p53 status and chr
    Type of Publication: Journal article published
    PubMed ID: 22265402
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: CANCER ; DISTINCT ; prognosis ; PROGRESSION ; chemotherapy ; ABERRATIONS ; MUTATIONS ; CHILDREN ; ADOLESCENTS ; INTRATUMOR HETEROGENEITY
    Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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). INTERPRETATION: 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. FUNDING: 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.
    Type of Publication: Journal article published
    PubMed ID: 24140199
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: CANCER ; CELLS ; DISTINCT ; CENTRAL-NERVOUS-SYSTEM ; METHYLATION ; ADULT ; BRAIN-TUMORS ; TELOMERASE ACTIVITY ; RISK STRATIFICATION ; SELF-RENEWAL
    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.
    Type of Publication: Journal article published
    PubMed ID: 24174164
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: SURVIVAL ; DIAGNOSIS ; prognosis ; CHILDREN ; RECURRENT ; TP53 mutation
    Abstract: BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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). CONCLUSIONS: 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.
    Type of Publication: Journal article published
    PubMed ID: 24616042
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: PROGRESSION ; EXPERIENCE ; papilloma ; ARTICLE
    Abstract: Purpose: To investigate molecular alterations in choroid plexus tumors (CPTs) using a genome-wide high-throughput approach, in order to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options. Experimental Design: One hundred CPTs were obtained from a multi-institutional database. Copy number (CN), DNA methylation and gene expression signatures were assessed for 74, 36 and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes. Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPCs) from choroid plexus papillomas (CPPs) and atypical choroid plexus papillomas (aCPPs). No significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis revealed two novel subgroups: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy (aUPD) events. We observed 60% of CPCs harbored TP53 mutations, and we identified a high-risk group of CPC patients carrying 2 mutant copies. These patients exhibited worse 5-year event-free (EFS) and overall survival (OS) compared to patients with CPC carrying 1 mutant copy (OS: 14.3%, 95% CI 0.71%-46.5% versus 66.7%, 28.2%-87.8%, respectively, p=0.04; EFS: 0% versus 44.4%, 13.6%-71.9%, respectively, p=0.03). CPPs and aCPPs exhibited favorable survival. Discussion: Our data demonstrates that distinct molecular signatures distinguish CPCs from CPPs and aCPPs; however molecular similarities among the papillomas suggest these two histological subgroups are indeed a single entity. A greater number of copies of mutated TP53 was significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs.
    Type of Publication: Journal article published
    PubMed ID: 25336695
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Abstract: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%+/-8.7%, respectively (p〈0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%+/-2% vs. 57.4%+/-1.8% (p〈0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p〈0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%+/-1.5% in lithium treated cells vs. 56.6+/-3% (p〈0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%+/-8% for lithium treated cells vs. 27%+/-3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
    Type of Publication: Journal article published
    PubMed ID: 25539912
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Abstract: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (〈5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (〈12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
    Type of Publication: Journal article published
    PubMed ID: 26760213
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...