TP53 Mutation Is Frequently Associated With CTNNB1 Mutation or MYCN Amplification and Is Compatible With Long-Term Survival in Medulloblastoma

Pfaff, Elke; Remke, Marc; Sturm, Dominik; Benner, Axel; Witt, Hendrik; Milde, Till; Bueren, André O. von; Wittmann, Andrea; Schöttler, A; Jorch, Norbert; Graf, Norbert; Kulozik, Andreas E.; Witt, Olaf; Scheurlen, Wolfram; Deimling, Andreas von; Rutkowski, Stefan; Taylor, Michael D.; Tabori, Uri; Lichter, Peter; Korshunov, Andrey; Pfister, Stefan M.

doi:10.1200/jco.2010.31.1670

Cited by 95 publications

(84 citation statements)

References 35 publications

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“…In addition, although somatic Trp53 mutations are found most frequently in WNT-MB, they have little prognostic significance in this subgroup. Therefore, subgroup identity remains the major predictor of prognosis for WNT-MB (16).…”

Section: Medulloblastomamentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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Section: Medulloblastomamentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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“…Of note, many mouse models of MB, including these MYC-driven group 3 models, require the loss of Trp53 function; yet somatic mutations of TP53 occur mostly in WNT and SHH medulloblastoma and are associated with MYCN rather than MYC amplification (Pfaff et al 2010;Rausch et al 2012). The absence of these mutations in group 3 tumors means that TP53 loss is not required for human tumor initiation, that another cooperative genetic event assists tumor initiation, or that the TP53 pathway is in some other way compromised.…”

Section: Myc In the Group 3 Subgroupmentioning

confidence: 99%

Role of MYC in Medulloblastoma

Roussel

Robinson

2013

Cold Spring Harbor Perspectives in Medicine

129

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Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.

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“…97 Examination of p53 gene status in 310 primary human MB tumors representing all 4 MB subgroups confirmed that p53 gene mutations in MB are rare and failed to correlate with chromosome 17p deletions. 96 In addition, this study yielded several novel insights. First, p53 gene mutations are overrepresented in MB tumors that have a mutation in the CTNNB1 gene (encoding β-catenin), indicative of Wnt activation, or that have a high level of NMYC amplification.…”

Section: Monographsmentioning

confidence: 83%

“…It has since been found that loss of 17p in MB and p53 status is unrelated. 88,96 New support for a role for p53 in MB tumorigenesis comes from a greater understanding of heterogeneity underlying MB tumors. Through the integration of molecular and clinical markers, including genetic abnormalities, patient age at time of diagnosis, tumor histology, and overall and progression-free survival, 4 MB subgroups with distinct signaling pathway alterations and clinicopathological features have been identified (see Table 1).…”

Section: Monographsmentioning

confidence: 99%

p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer

2011

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The p53 tumor suppressor potently limits the growth of immature and mature neurons under conditions of cellular stress. Although loss of p53 function contributes to the pathogenesis of central nervous system (CNS) tumors, excessive p53 function is implicated in neural tube defects, embryonic lethality, and neuronal degeneration. Thus, p53 function must be tightly controlled. The anti-proliferative properties of p53 are mediated, in part, through the induction of apoptosis, cell cycle arrest, and senescence. Although there is still much to be learned about the role of p53 in these processes, recent evidence supports exciting new roles for p53 in a wide range of processes, including neural precursor cell self-renewal, differentiation, and cell fate decisions. Understanding the full repertoire of p53 function in CNS development and tumorigenesis may provide us with novel points of therapeutic intervention for human diseases of the CNS.

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TP53 Mutation Is Frequently Associated With CTNNB1 Mutation or MYCN Amplification and Is Compatible With Long-Term Survival in Medulloblastoma

Cited by 95 publications

References 35 publications

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Role of MYC in Medulloblastoma

p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer

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