Article

Universal Poor Survival in Children With Medulloblastoma Harboring Somatic TP53 Mutations

Divisions of Haematology/Oncology, The LabattBrain Tumor Research Centre, TheHospital for Sick Children, Toronto, Ontario, Canada.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2010; 28(8):1345-50. DOI: 10.1200/JCO.2009.23.5952
Source: PubMed

ABSTRACT

Medulloblastoma is the prototype of treatment success in modern pediatric neuro-oncology. Unfortunately, 20% to 30% of tumors recur despite maximal resection and multimodal therapy. Multiple biologic prognostic markers have been investigated to predict recurrences, but controversy remains regarding their clinical utility. Because p53 immunopositivity is an adverse prognostic marker in pediatric medulloblastoma and TP53 mutations are associated with chemotherapy and radiation therapy resistance, we aimed to determine the extent and role of TP53 mutations in pediatric medulloblastoma treatment failure.
One hundred eight of 111 consecutive patients diagnosed with medulloblastoma in our institution from 1995 to 2007 were included. Median follow-up time was 5.3 years in survivors. All samples were immunostained for p53 and erbB-2. Histologic grade and immunostaining were scored by two blinded reviewers. For 49 patients, frozen material was available for TP53 sequencing. The main outcome measures were overall and progression-free survival.
Sixteen percent of sequenced medulloblastomas harbored a TP53 mutation. As a screening test, p53 immunohistochemistry was 100% sensitive and 83% specific for a TP53 mutation. Strikingly, all mutated tumors recurred early, and 5-year survival for average-risk patients was 0% for TP53-mutated medulloblastoma compared with 74% +/- 8% for wild-type medulloblastoma (P < .0001). Furthermore, 75% of recurrences in average-risk patients were associated with TP53 mutations. On multivariate analysis, TP53 mutation status was the strongest adverse prognostic factor (hazard ratio = 10.4, P = .003).
Lack of long-term survival in TP53-mutated medulloblastomas highlights the role of TP53 mutations in medulloblastoma resistance to conventional therapies and the need for alternative treatments, and prospective validation of these findings is needed.

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    • "These patients account for the majority of treatment failures within the SHH subgroup, and they are also the subset of SHH patients least likely to respond to targeted SHH inhibitors. TP53- mutated SHH medulloblastomas commonly harbor downstream genetic events, including MYCN and GLI2 amplifications, which will likely result in resistance to current SHH inhibitors (e.g., vismodegib and sonidegib, which target Smoothened) in phase II clinical trials (Pfaff et al. 2010; Tabori et al. 2010; Gajjar et al. 2013; Kool et al. 2014; Shou et al. 2015). As such, successful therapeutic targeting of this group will require the identification of SHH pathway inhibitors, which act downstream from either MYCN or GLI2. "
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    ABSTRACT: Our understanding of medulloblastoma biology has increased dramatically over the past decade, in part a result of the recognition that there exists tremendous intertumoral heterogeneity not apparent by morphology alone. A particular area that significantly changed our approach to medulloblastoma has been an increased understanding of the role of p53. A role for p53 in medulloblastoma has been established over the past 20 years, however, not until recently has its significance been identified. Recent developments in the understanding of intertumor heterogeneity has clarified the role of TP53 mutations, as the importance of TP53 mutations is highly dependent on the molecular subgroup of medulloblastoma, with TP53 mutant Sonic Hedgehog medulloblastomas forming an extremely high-risk group of patients. As such, there is now a tremendous push to understand the role that p53 plays in treatment resistance of medulloblastoma. In this review, we will summarize the current understanding of p53 in medulloblastoma drawn primarily from recent advances in integrated genomics.
    Preview · Article · Dec 2015 · Cold Spring Harbor Perspectives in Medicine
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    • "The loss of TP53 due to the loss of chromosome 17p and isochromosome 17q are the most prevalent chromosomal abnormalities observed in MB [33]–[35]. Mutations in TP53 were found in 16% of MB and this is associated with a poor 5 year survival rate [36]. We have previously reported that p53 mutations in MB cell lines are also associated with increased drug resistance, which is likely to be, at least in part, responsible for the worse prognosis observed in patient with p53 mutations [8]. "
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    ABSTRACT: Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma) and adult (glioblastoma) brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs) have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1). Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Although immunostaining does not allow to distinguish wild-type from mutated p53, expression of p53 is often used as a surrogate marker for alterations in the functional status of p53. Indeed, a recent study using the same antibody as our, showed that, in clinical medulloblastoma samples, high levels of detectable p53 protein may correlate with point mutations [39]. Thus, we examined p53 protein expression in tumors from each experimental group, as indicator of an aggressive phenotype. "
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    ABSTRACT: Background The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis. Methods In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice. Results A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females. Conclusion We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.
    Full-text · Article · Jul 2014 · PLoS ONE
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