Universal Poor Survival in Children With Medulloblastoma Harboring Somatic TP53 Mutations
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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ABSTRACT: We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cancer Cell 12/2014; 27(1):72-84. DOI:10.1016/j.ccell.2014.11.002 · 23.89 Impact Factor
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ABSTRACT: The design of medulloblastoma therapy has become more and more sophisticated over the past 30 years. Despite this, a significant proportion of patients continue to die from this disease, with drug resistance and relapse still observed. Resistance to treatment with anticancer drugs results from a variety of factors including individual genetic variations in patients and acquired resistance. We here review the most common reasons for drug resistance in medulloblastoma cells. We will cover the acquisition of drug resistance towards the classical chemotherapeutic drugs used in medulloblastoma due to modification of enzymatic activities such as alkyl tranferase, gluthatione tranferase, phosphatidyl-inositol-3-kinase or to expression of energy-dependent transporters that eject anticancer drugs from cells. We will also review other mechanisms of resistance including insensitivity to drug-induced cell death due to genetic mutations in crucial signaling pathways such as NF-kappaB and p53.Tumors of the Central Nervous System, Volume 8, Edited by Hayat, M. A., 01/2012: pages 59-69; Springer Netherlands.
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ABSTRACT: The diagnosis of pediatric medulloblastoma now carries a much improved overall survival; however as outcomes advance, late mortality, from causes such as disease recurrence and subsequent malignancies, are of increasing concern for these patients. Using the Surveillance, Epidemiology, and End Results database, the causes of late mortality in long term survivors of medulloblastoma were evaluated. Patients diagnosed with a medulloblastoma between the ages of 0–19 years who survived at least 5 years after diagnosis were included. Using U.S. population data, standardized mortality ratios (SMRs) were calculated. Cumulative incidence estimates and standardized incidence ratios (SIRs) of subsequent malignancies were calculated. A total of 455 patients were included in the analysis. All patients received radiation as part of therapy. Median age at diagnosis was 7 years, and mean follow-up was 16 years. By the time of last follow-up, 20.4 % of patients had died, representing an SMR of 24.0 (95 % CI 19.3–29.4). Overall survival at 30 years was 65.5 %. Primary recurrence accounted for 59 % of late deaths, while subsequent malignancy accounted for 11.8 %. SIR for subsequent malignancy in these patients was 10.4 (95 % CI 6.9–15.1). The most common secondary tumor was another brain tumor (32 %), followed by thyroid cancer (21 %). These data demonstrate that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk stratification and tailor therapy will help in reducing late mortality in this population.Journal of Neuro-Oncology 01/2015; 122(2). DOI:10.1007/s11060-014-1712-y · 2.79 Impact Factor