β-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee

Ellison, David W.; Onilude, Olabisi E.; Lindsey, John H.; Lusher, Meryl E.; Weston, Claire; Taylor, Roger; Pearson, Andrew D.J.; Clifford, Steven C.

doi:10.1200/jco.2005.01.5479

Cited by 393 publications

(292 citation statements)

References 32 publications

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“…Cytogenetic aberrations in MB involving chromosome 17 as well as ampliWcations of the MYC or MYCN oncogenes have previously been associated with large cell histology and poor patient survival in diVerent studies [6,7,9,11,13,15,17,18,23,24]. In contrast, several recent reports have identiWed monosomy of chromosome 6 to be associated with consecutive WNT pathway activation and favorable clinical outcome [2,8,25].…”

Section: Introductionmentioning

confidence: 85%

Accumulation of genomic aberrations during clinical progression of medulloblastoma

et al. 2008

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Medulloblastomas comprise the most frequent malignant brain tumor in childhood and one of the biggest challenges in pediatric oncology. The current concept suggests that these tumors may undergo stepwise progression as it has been shown for other brain tumors. However, conclusive evidence of molecular progression over time has not been demonstrated yet for medulloblastoma. In the present study, 28 pairs of medulloblastoma at primary diagnosis and at the time of recurrence, either occurring as local tumor regrowth or tumor dissemination, were histopathologically and molecularly analyzed. Cytogenetic analysis included interphase Xuorescence in situ hybridization for Wve genomic loci (MYC, MYCN, 17p, 17q, 6q) that have previously been identiWed as prognostic markers in primary tumors. Of 16 tumors showing early recurrence (<4 years after Wrst diagnosis), only one showed increased histological anaplasia in the secondary lesion (6%), and two acquired genomic lesions indicative for a more malignant phenotype (13%). In contrast to this, of 12 tumors with a time to recurrence of 4 years or more, nine tumors (75%) showed a more malignant phenotype either reXected by increased anaplasia alone or by both increased anaplasia and acquirement of genomic aberrations known to be associated with inferior patient outcome. These results suggest that early recurrence in medulloblastoma mainly occurs in tumors with a highly malignant genotype and phenotype per se, whereas late recurrence is often dependent on tumor evolution toward a more malignant biology. Therefore, biopsy of recurrent tumors should be performed to assess the biologic properties of the relapsed tumor, especially when targeted therapy approaches are considered.

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Section: Introductionmentioning

confidence: 85%

Accumulation of genomic aberrations during clinical progression of medulloblastoma

et al. 2008

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“…Medulloblastoma subtypes A and B are characterized by exclusive aberrant activation of the Wnt and Shh signaling pathways, respectively. Activation of the Wnt signaling pathway characterizes a distinct molecular subgroup of medulloblastomas associated with a favorable prognosis (Ellison et al, 2005;Fattet et al, 2009). In contrast, medulloblastoma molecular subtypes C and D are associated with metastatic disease and poor patient outcome (Northcott et al, 2010).…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 99%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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“…Similar to the characterization of the Shh signaling pathway in MB, Wnt signaling was first implicated in the pathogenesis of MB by its activation in a familial cancer syndrome-Turcot syndrome (53). Mutations in several members of the Wnt pathway have since been identified in MB, accounting for 25% of sporadic MB (5,(31)(32)(33). These include activating mutations in CTNNB1 (which codes for β-catenin) and inactivating mutations in APC and Axin (54)(55)(56).…”

Section: Wnt Subtype Mbmentioning

confidence: 99%

“…These include activating mutations in CTNNB1 (which codes for β-catenin) and inactivating mutations in APC and Axin (54)(55)(56). Of interest, such mutations characteristic of Wnt subtype MB patients are associated with an improved survivorship as compared with all other subtypes, including Shh-driven MB (31)(32)(33). The first mouse model of the human Wnt MB subgroup was created in the past year; Gibson et al (57) identified genes marking the human Wnt subtype to be more frequently expressed in the lower rhombic lip and embryonic dorsal brainstem than the upper rhombic lip.…”

Section: Wnt Subtype Mbmentioning

confidence: 99%

“…Unsupervised hierarchical clustering methods of segregating these data have produced four or five subgroups, two of which (subtypes A and B) are characterized by upregulation of genes in the Wingless (Wnt) or Sonic hedgehog (Shh) pathways, respectively. These two subgroups are separated from each other and other subgroups on principal components analysis and both are associated with improved clinical outcomes as compared with subtypes C, D, and E, which are characterized by a greater propensity for metastatic disease and poor clinical outcomes (3)(4)(5)(31)(32)(33). These aggressive MBs are collectively known as "non-Shh/Wnt" subtypes, which remain refractory to current treatment modalities and are without aberrant activation of specific signaling pathways, possibly suggesting the involvement of novel BTIC self-renewal genes and pathways (Figure 1) (34).…”

Section: Reviewmentioning

confidence: 99%

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Medulloblastoma stem cells: where development and cancer cross pathways

et al. 2012

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Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (csc) populations, termed brain tumor-initiating cells (BTIcs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, sonic hedgehog (shh) and Wingless (Wnt), along with the identification of novel BTIc self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTIcs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options.

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β-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee

Abstract: Nuclear accumulation of beta-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.

Cited by 393 publications

References 32 publications

Accumulation of genomic aberrations during clinical progression of medulloblastoma

Accumulation of genomic aberrations during clinical progression of medulloblastoma

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Medulloblastoma stem cells: where development and cancer cross pathways

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