Medulloblastomics: the end of the beginning

The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies.

[1]  David Hogg,et al.  Mutations in SUFU predispose to medulloblastoma , 2002, Nature Genetics.

[2]  Dirk Troost,et al.  Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features , 2008, PloS one.

[3]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[4]  Eric Bouffet,et al.  Core neurocognitive functions in children treated for posterior fossa tumors. , 2008, Neuropsychology.

[5]  J. Drake,et al.  Medulloblastoma in a Child with Rubenstein-Taybi Syndrome: Case Report and Review of the Literature , 2001, Pediatric Neurosurgery.

[6]  M. Roussel,et al.  A mouse model of the most aggressive subgroup of human medulloblastoma. , 2012, Cancer cell.

[7]  Lawrence A. Donehower,et al.  Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D , 2007, Journal of Neuro-Oncology.

[8]  Arie Perry,et al.  Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups , 2011, Acta Neuropathologica.

[9]  J Alter,et al.  Progress and Promise , 1919, Nature.

[10]  J. Uhm Medulloblastoma Comprises Four Distinct Molecular Variants , 2011 .

[11]  J. Helms,et al.  CHD7 cooperates with PBAF to control multipotent neural crest formation , 2010, Nature.

[12]  M. Scott,et al.  Altered neural cell fates and medulloblastoma in mouse patched mutants. , 1997, Science.

[13]  J. Uhm Clonal selection drives genetic divergence of metastatic medulloblastoma , 2012 .

[14]  P. Burger,et al.  Nuclear Localization and Mutation of β‐Catenin in Medulloblastomas , 2000 .

[15]  O. Kepp,et al.  Preferential killing of tetraploid tumor cells by targeting the mitotic kinesin Eg5 , 2009, Cell cycle.

[16]  Axel Benner,et al.  Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  P. Northcott,et al.  Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. , 2012, Cancer cell.

[18]  Yan-Hwa Wu Lee,et al.  The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. , 2008, Molecular biology of the cell.

[19]  D. Pellman,et al.  From polyploidy to aneuploidy, genome instability and cancer , 2004, Nature Reviews Molecular Cell Biology.

[20]  B. Hinkes,et al.  Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91. , 2009, European journal of cancer.

[21]  G. Hendson,et al.  Interphase fluorescence in situ hybridization and DNA flow cytometry analysis of medulloblastomas with a normal karyotype. , 2002, Cancer genetics and cytogenetics.

[22]  J. Rutka,et al.  Molecular Insight into Medulloblastoma and Central Nervous System Primitive Neuroectodermal Tumor Biology from Hereditary Syndromes: A Review , 2000, Neurosurgery.

[23]  W. Blattner,et al.  Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li–Fraumeni syndrome , 1990, Nature.

[24]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[25]  L. Zitvogel,et al.  Selective Resistance of Tetraploid Cancer Cells against DNA Damage‐Induced Apoptosis , 2006, Annals of the New York Academy of Sciences.

[26]  J. Schwabe,et al.  Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery , 2011, Nature Structural &Molecular Biology.

[27]  G. Rao,et al.  WIP1 Enhances Tumor Formation in a Sonic Hedgehog–Dependent Model of Medulloblastoma , 2012, Neurosurgery.

[28]  R. Stephens,et al.  The Identification of MicroRNAs in a Genomically Unstable Region of Human Chromosome 8q24 , 2008, Molecular Cancer Research.

[29]  J. Huse,et al.  Genetically Engineered Mouse Models of Brain Cancer and the Promise of Preclinical Testing , 2008, Brain pathology.

[30]  F. Berthold,et al.  Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. , 2001, Cancer research.

[31]  R. Myers,et al.  Human Homolog of patched, a Candidate Gene for the Basal Cell Nevus Syndrome , 1996, Science.

[32]  N. Grishin,et al.  Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway* , 2011, The Journal of Biological Chemistry.

[33]  Zev A. Binder,et al.  The Genetic Landscape of the Childhood Cancer Medulloblastoma , 2011, Science.

[34]  R. Packer Risk Stratification of Medulloblastoma: A Paradigm for Future Childhood Brain Tumor Management Strategies , 2011, Current neurology and neuroscience reports.

[35]  V. Capra,et al.  Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective , 2009, Clinical Cancer Research.

[36]  K. Kinzler,et al.  The molecular basis of Turcot's syndrome. , 1995, The New England journal of medicine.

[37]  S. Croul,et al.  Adult medulloblastoma comprises three major molecular variants. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Z. Modrušan,et al.  Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. , 2011, Cancer research.

[39]  Claire L Weston,et al.  beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  R. McLendon,et al.  OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. , 2010, Cancer research.

[41]  M. Schröder Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation. , 2010, Biochemical pharmacology.

[42]  Michael Dean,et al.  Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome , 1996, Cell.

[43]  M. Clementi,et al.  Identification of a SUFU germline mutation in a family with Gorlin syndrome , 2009, American journal of medical genetics. Part A.

[44]  T. Poggio,et al.  Prediction of central nervous system embryonal tumour outcome based on gene expression , 2002, Nature.

[45]  Paul A. Northcott,et al.  Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct , 2011, Acta Neuropathologica.

[46]  P. Northcott,et al.  Molecular subgroups of medulloblastoma , 2012, Expert review of neurotherapeutics.

[47]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[48]  Elaine R. Mardis,et al.  Novel mutations target distinct subgroups of medulloblastoma , 2012, Nature.

[49]  Axel Benner,et al.  Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  T. Gehr,et al.  Case Report and Review of the Literature: Ureteral Endometriosis , 1987, The American journal of the medical sciences.

[51]  A. Sivachenko,et al.  Sequence analysis of mutations and translocations across breast cancer subtypes , 2012, Nature.

[52]  Axel Benner,et al.  FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  Joel I. Pritchard,et al.  The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. , 2008, Cancer research.

[54]  R. Packer,et al.  Management of and prognosis with medulloblastoma: therapy at a crossroads. , 2008, Archives of neurology.

[55]  Wen-Lin Kuo,et al.  Amplification of PVT1 Contributes to the Pathophysiology of Ovarian and Breast Cancer , 2007, Clinical Cancer Research.

[56]  Scott L. Pomeroy,et al.  Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas , 2012, Acta Neuropathologica.

[57]  P. Cogen,et al.  Deletion mapping of the medulloblastoma locus on chromosome 17p. , 1990, Genomics.

[58]  Kristian Helin,et al.  Molecular mechanisms and potential functions of histone demethylases , 2012, Nature Reviews Molecular Cell Biology.

[59]  Fatih Ozsolak,et al.  RNA sequencing: advances, challenges and opportunities , 2011, Nature Reviews Genetics.

[60]  D. Ellison,et al.  TP53 mutations in favorable-risk Wnt/Wingless-subtype medulloblastomas. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  D. Ellison,et al.  Wnt/Wingless Pathway Activation and Chromosome 6 Loss Characterise a Distinct Molecular Sub-Group of Medulloblastomas Associated with a Favourable Prognosis , 2006, Cell cycle.

[62]  A. Berns,et al.  Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. , 2000, Genes & development.

[63]  T. Curran,et al.  Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  D. Malkin,et al.  Hereditary cancer predisposition in children: Genetic basis and clinical implications , 2006, International journal of cancer.

[65]  D. Figarella-Branger,et al.  Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  J. Uhm An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2009 .

[67]  D. Grzybicki,et al.  Subtypes of medulloblastoma have distinct developmental origins , 2012 .

[68]  F. D. de Sauvage,et al.  Clinical experience with Hedgehog pathway inhibitors. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  P. Worley,et al.  Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions , 1999, Nature Genetics.

[70]  M. Greene,et al.  Developmental defects in gorlin syndrome related to a putative tumor suppressor gene on chromosome 9 , 1992, Cell.

[71]  Johannes Zuber,et al.  A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA Interference , 2011, Cell.

[72]  Scott L. Pomeroy,et al.  Molecular subgroups of medulloblastoma: the current consensus , 2011, Acta Neuropathologica.

[73]  V. Sheffield,et al.  Involvement of multiple chromosome 17p loci in medulloblastoma tumorigenesis. , 1992, American journal of human genetics.

[74]  T. Tomita,et al.  Bone metastases of medulloblastoma in childhood; correlation with flow cytometric DNA analysis , 1990, Journal of Neuro-Oncology.

[75]  W. Lam,et al.  Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. , 2012, Cancer genetics.

[76]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[77]  J. Dixon,et al.  A conserved phosphatase cascade that regulates nuclear membrane biogenesis , 2007, Proceedings of the National Academy of Sciences.

[78]  J. Olson,et al.  The molecular classification of medulloblastoma: driving the next generation clinical trials , 2012, Current opinion in pediatrics.

[79]  T. Curran,et al.  Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. , 2008, Cancer cell.

[80]  N. Caplen,et al.  Pvt1-encoded microRNAs in oncogenesis , 2008, Retrovirology.

[81]  K. Chrzanowska,et al.  Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients , 2010, Acta Neuropathologica.

[82]  C. Raffel,et al.  Sporadic Medulloblastomas Contain Oncogenic β-Catenin Mutations , 1998 .

[83]  G. Grabenbauer,et al.  Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. , 2003, Medical and pediatric oncology.

[84]  C. Eberhart Three down and one to go: modeling medulloblastoma subgroups. , 2012, Cancer cell.

[85]  David Pellman,et al.  Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells , 2005, Nature.

[86]  Lusy Handoko,et al.  CHD7 Targets Active Gene Enhancer Elements to Modulate ES Cell-Specific Gene Expression , 2010, PLoS genetics.

[87]  Ching-Hon Pui,et al.  Challenging issues in pediatric oncology , 2011, Nature Reviews Clinical Oncology.

[88]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[89]  C. Ross,et al.  Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease , 2001, Nature Medicine.

[90]  G. Rao The miR-17/92 Polycistron Is Up-regulated in Sonic Hedgehog–Driven Medulloblastomas and Induced by N-myc in Sonic Hedgehog–Treated Cerebellar Neural Precursors , 2010 .

[91]  M. Kool,et al.  Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem , 2012, Acta Neuropathologica.

[92]  T Pietsch,et al.  Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. , 1997, Cancer research.

[93]  Th. Boveri Concerning the Origin of Malignant Tumours by Theodor Boveri. Translated and annotated by Henry Harris , 2008, Journal of Cell Science.

[94]  G. Parmigiani,et al.  Design and analysis issues in genome-wide somatic mutation studies of cancer. , 2009, Genomics.

[95]  L. Chin,et al.  Making sense of cancer genomic data. , 2011, Genes & development.

[96]  A. Sivachenko,et al.  A Landscape of Driver Mutations in Melanoma , 2012, Cell.

[97]  Tom Koch Advances, Challenges and Opportunities in Silicon Photonics , 2007 .

[98]  Robert Machold,et al.  Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. , 2008, Cancer cell.

[99]  P. Burger,et al.  “Desmoplastic” versus “classic” medulloblastoma: Comparison of DNA content, histopathology and differentiation , 2005, Virchows Archiv A.

[100]  M. Dawson,et al.  Cancer Epigenetics: From Mechanism to Therapy , 2012, Cell.

[101]  S. Vandenberg,et al.  Pleiotropic role for MYCN in medulloblastoma. , 2010, Genes & development.

[102]  C. Rudin,et al.  Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma , 2009, Science.

[103]  D. Bulavin,et al.  WIP1 phosphatase at the crossroads of cancer and aging. , 2010, Trends in biochemical sciences.

[104]  David T. W. Jones,et al.  Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations , 2012, Cell.

[105]  Ji-Joon Song,et al.  Diverse ways to be specific: a novel Zn-binding domain confers substrate specificity to UTX/KDM6A histone H3 Lys 27 demethylase. , 2011, Genes & development.

[106]  P. Varlet,et al.  Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations , 2009, Journal of Medical Genetics.

[107]  Jing Yuan,et al.  Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma , 2010, Science Translational Medicine.

[108]  A. Sivachenko,et al.  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer , 2012, Nature Genetics.

[109]  P. Kleihues,et al.  AXIN1 mutations but not deletions in cerebellar medulloblastomas , 2003, Oncogene.

[110]  T. Curran,et al.  The Hedgehog's tale: developing strategies for targeting cancer , 2011, Nature Reviews Cancer.

[111]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[112]  R. Packer Childhood Brain Tumors: Accomplishments and Ongoing Challenges , 2008, Journal of child neurology.

[113]  Eric Bouffet,et al.  Change in neurocognitive functioning after treatment with cranial radiation in childhood. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[114]  P. Febbo,et al.  An animal model of MYC-driven medulloblastoma. , 2012, Cancer cell.

[115]  M. Stratton Exploring the Genomes of Cancer Cells: Progress and Promise , 2011, Science.

[116]  Stefan M. Pfister,et al.  The clinical implications of medulloblastoma subgroups , 2012, Nature Reviews Neurology.

[117]  T. Curran,et al.  The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. , 2000, Cancer research.

[118]  S. Yokoyama,et al.  Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A. , 2011, Genes & development.

[119]  P. Northcott,et al.  Targeting the enhancer of zeste homologue 2 in medulloblastoma , 2012, International journal of cancer.

[120]  M. Scott,et al.  Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog , 1999, Neuron.

[121]  D. Ellison,et al.  Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. , 2005, European journal of cancer.

[122]  J. Little,et al.  Family cancer history and risk of brain tumors in children: results of the SEARCH international brain tumor study , 2008, Cancer Causes & Control.

[123]  A. McCullough Comprehensive molecular characterization of human colon and rectal cancer , 2013 .

[124]  Roger E. Taylor,et al.  Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[125]  Paul A. Northcott,et al.  Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma , 2009, Nature Genetics.

[126]  Scott L. Pomeroy,et al.  Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples , 2011, Acta Neuropathologica.

[127]  F. McCormick,et al.  A frequent activated smoothened mutation in sporadic basal cell carcinomas , 1999, Oncogene.

[128]  R. Gelber,et al.  Prognostic factors in medulloblastoma, including DNA ploidy. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[129]  G. Reifenberger,et al.  BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. , 2008, The Journal of clinical investigation.

[130]  David T. W. Jones,et al.  Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. , 2008, Cancer research.

[131]  T. Hongo,et al.  Chromosome analysis of brain tumors in childhood , 1994, Genes, chromosomes & cancer.

[132]  M. Asashima,et al.  Dullard promotes degradation and dephosphorylation of BMP receptors and is required for neural induction. , 2006, Developmental cell.

[133]  E. Greer,et al.  Histone methylation: a dynamic mark in health, disease and inheritance , 2012, Nature Reviews Genetics.

[134]  Joel I. Pritchard,et al.  The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas , 2004, Cancer Research.

[135]  Mark L. Greenberg,et al.  Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[136]  Jeremy Stinson,et al.  Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. , 2009, The New England journal of medicine.

[137]  Paul Flicek,et al.  The functional spectrum of low-frequency coding variation , 2011, Genome Biology.

[138]  N. Carter,et al.  Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development , 2011, Cell.

[139]  M. Högbom,et al.  Crystal structure of conserved domains 1 and 2 of the human DEAD-box helicase DDX3X in complex with the mononucleotide AMP. , 2007, Journal of molecular biology.

[140]  S. Croul,et al.  Mouse models of medulloblastoma , 2011, Chinese journal of cancer.

[141]  T. Merchant,et al.  Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. , 2006, The Lancet. Oncology.

[142]  G. E. Keles,et al.  Establishment and characterization of four human medulloblastoma-derived cell lines. , 1995, Oncology research.

[143]  T. Davoli,et al.  Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. , 2012, Cancer cell.

[144]  J. Kessler,et al.  Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma , 2005, Development.

[145]  R. Gilbertson,et al.  Mapping Cancer Origins , 2011, Cell.

[146]  Tao Sun,et al.  Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. , 2008, Cancer cell.

[147]  N. Copeland,et al.  Harnessing transposons for cancer gene discovery , 2010, Nature Reviews Cancer.

[148]  S. Gabriel,et al.  Advances in understanding cancer genomes through second-generation sequencing , 2010, Nature Reviews Genetics.

[149]  David Pellman,et al.  Causes and consequences of aneuploidy in cancer , 2012, Nature Reviews Genetics.

[150]  J. Biegel,et al.  Evidence for a 17p tumor related locus distinct from p53 in pediatric primitive neuroectodermal tumors. , 1992, Cancer research.

[151]  S. Engelender,et al.  Synphilin Isoforms and the Search for a Cellular Model of Lewy Body Formation in Parkinson's Disease , 2006, Cell cycle.

[152]  L. Galluzzi,et al.  Inhibition of Chk1 Kills Tetraploid Tumor Cells through a p53-Dependent Pathway , 2007, PloS one.

[153]  G. Crawford,et al.  Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. , 2009, Genome research.

[154]  Matthew J. Betts,et al.  Dissecting the genomic complexity underlying medulloblastoma , 2012, Nature.

[155]  P. Lichter,et al.  TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[156]  B. Rinkevich,et al.  The DDX3 subfamily of the DEAD box helicases: divergent roles as unveiled by studying different organisms and in vitro assays. , 2007, Current medicinal chemistry.

[157]  M. Wolter,et al.  Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. , 1997, Cancer research.

[158]  Christof Fellmann,et al.  Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi , 2011, Nature Biotechnology.

[159]  F. Berthold,et al.  Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF‐dependent transcription in medulloblastomas , 2007, International journal of cancer.

[160]  P. Northcott,et al.  Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years. , 2010, Neurosurgical focus.

[161]  P. Varlet,et al.  High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[162]  Peter A. Jones,et al.  A decade of exploring the cancer epigenome — biological and translational implications , 2011, Nature Reviews Cancer.

[163]  Y. Nakamura,et al.  Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. , 1999, Human molecular genetics.

[164]  J. Mesirov,et al.  Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[165]  Steven J. M. Jones,et al.  Subgroup-specific structural variation across 1,000 medulloblastoma genomes , 2012, Nature.

[166]  F. D. de Sauvage,et al.  Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. , 2011, Cancer research.

[167]  Jill P. Mesirov,et al.  MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS , 2012, Nature.

[168]  Mark P. Jedrychowski,et al.  Human DDX3 functions in translation and interacts with the translation initiation factor eIF3 , 2008, Nucleic acids research.

[169]  Min Gyu Lee,et al.  An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation , 2005, Nature.

[170]  C. James,et al.  Sporadic medulloblastomas contain PTCH mutations. , 1997, Cancer research.

[171]  S. Shieh,et al.  DDX3 Regulates Cell Growth through Translational Control of Cyclin E1 , 2010, Molecular and Cellular Biology.

[172]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[173]  Jun Wei Pek,et al.  DEAD-box RNA helicase Belle/DDX3 and the RNA interference pathway promote mitotic chromosome segregation , 2011, Proceedings of the National Academy of Sciences.

[174]  M. Stratton,et al.  The cancer genome , 2009, Nature.