The Genetic Landscape of the Childhood Cancer Medulloblastoma

Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Science (Impact Factor: 33.61). 01/2011; 331(6016):435-9. DOI: 10.1126/science.1198056
Source: PubMed


Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor
type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes
and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations,
fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in
the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most
notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB
patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight
dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type
of histone methylation in human tumorigenesis.

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    • "Recent genome-wide studies have identified mutations in genes for the regulators of enhancer chromatin in cancer (Herz et al. 2014a). Mutations of the H3K4 monomethylases MLL3 and MLL4 as well as their cofactor, UTX, within the COMPASS family have been identified in a range of malignancies, including the pediatric brain cancer medulloblastoma (Parsons et al. 2011; Jones et al. 2012; Pugh et al. 2012), non-Hodgkin lymphoma (Morin et al. 2011; Pasqualucci et al. 2011; Lohr et al. 2012), and bladder cancer (Gui et al. 2011). MLL4 is particularly frequently mutated in non-Hodgkin lymphomas and often co-occurs with mutations in the histone acetyltransferase gene CREBBP and activating mutations of EZH2 (Morin et al. 2011; Okosun et al. 2014). "
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    ABSTRACT: Changes in the pattern of gene expression play an important role in allowing cancer cells to acquire their hallmark characteristics, while genomic instability enables cells to acquire genetic alterations that promote oncogenesis. Chromatin plays central roles in both transcriptional regulation and the maintenance of genomic stability. Studies by cancer genome consortiums have identified frequent mutations in genes encoding chromatin regulatory factors and histone proteins in human cancer, implicating them as major mediators in the pathogenesis of both hematological malignancies and solid tumors. Here, we review recent advances in our understanding of the role of chromatin in cancer, focusing on transcriptional regulatory complexes, enhancer-associated factors, histone point mutations, and alterations in heterochromatin-interacting factors. © 2015 Morgan and Shilatifard; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 02/2015; 29(3):238-249. DOI:10.1101/gad.255182.114 · 10.80 Impact Factor
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    • "Alternatively, MLL1 may be required to mediate local chromatin modifications that enable the subsequent recruitment of JMJD3 to specific genomic regions . The discovery of this genetic interaction may provide insights into how mutations in MLL genes and H3K27me3-specific demethylases contribute to the transcriptional dysregulation of medulloblastomas (Jones et al., 2012; Parsons et al., 2011). "
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    ABSTRACT: The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
    Cell Reports 08/2014; 8(5). DOI:10.1016/j.celrep.2014.07.060 · 8.36 Impact Factor
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    • "Other histone methylases/acteylases, such as HDAC5, HDAC9, MLL2, and MLL3, have also been found to be over-expressed in medulloblastomas, but in these studies the authors did not investigate their prevalence in individual subgroups (34, 36). Interestingly, the HDAC5 gene locus is located on chromosome 17q, which is commonly amplified in group 4 tumors (34, 36). "
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    ABSTRACT: As advances in the molecular and genetic profiling of pediatric medulloblastoma evolve, associations with prognosis and treatment are found (prognostic and predictive biomarkers) and research is directed at molecular therapies. Medulloblastoma typically affects young patients, where the implications of any treatment on the developing brain must be carefully considered. The aim of this article is to provide a clear comprehensible update on the role molecular profiling and subgroups in pediatric medulloblastoma as it is likely to contribute significantly toward prognostication. Knowledge of this classification is of particular interest because there are new molecular therapies targeting the Shh subgroup of medulloblastomas.
    Frontiers in Oncology 07/2014; 4:176. DOI:10.3389/fonc.2014.00176
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