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Current Neurology and Neuroscience Reports

Published in:

01-05-2010

The Genetics of Pediatric Brain Tumors

Authors: Adrian M. Dubuc, Paul A. Northcott, Stephen Mack, Hendrik Witt, Stefan Pfister, Michael D. Taylor

Published in: Current Neurology and Neuroscience Reports | Issue 3/2010

Abstract

Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.

Crawford JR, MacDonald TJ, Packer RJ: Medulloblastoma in childhood: new biological advances. Lancet Neurol 2007, 6:1073–1085.CrossRefPubMed

Gilbertson RJ, Ellison DW: The origins of medulloblastoma subtypes. Annu Rev Pathol 2008, 3:341–365.CrossRefPubMed

Taylor MD, Mainprize TG, Rutka JT: Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 2000, 47:888–901.CrossRefPubMed

Hahn H, Wicking C, Zaphiropoulous PG, et al.: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996, 85:841–851.CrossRefPubMed

Marino S: Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 2005, 11:17–22.CrossRefPubMed

Hamilton SR, Liu B, Parsons RE, et al.: The molecular basis of Turcot’s syndrome. N Engl J Med 1995, 332:839–847.CrossRefPubMed

Srivastava S, Zou ZQ, Pirollo K, et al.: Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990, 348:747–749.CrossRefPubMed

Ray A, Ho M, Ma J, et al.: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 2004, 10:7613–7620.CrossRefPubMed

•• Northcott PA, Nakahara Y, Wu X, et al.: Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 2009, 41:465–472. The largest high-resolution genomic profiling of pediatric brain tumors performed to date identified and characterized a novel mechanism by which medulloblastomas may deregulate the transcriptome through aberrant histone modifications.CrossRefPubMed

10.

• Pfister S, Remke M, Benner A, et al.: Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 2009, 27:1627–1636. Pfister et al. identified an elegant molecular stratification system for medulloblastomas based on the DNA copy number status of only four genomic loci.CrossRefPubMed

11.

Pan E, Pellarin M, Holmes E, et al.: Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 2005, 11:4733–4740.CrossRefPubMed

12.

Northcott PA, Fernandez LA, Hagan JP, et al.: 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. Cancer Res 2009, 69:3249–3255.CrossRefPubMed

13.

Uziel T, Karginov FV, Xie S, et al.: The miR-17 ∼ 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci U S A 2009, 106:2812–2817.CrossRefPubMed

14.

Clifford SC, Lusher ME, Lindsey JC, et al.: Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 2006, 5:2666–2670.PubMed

15.

Gajjar A, Chintagumpala M, Ashley D, 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. Lancet Oncol 2006, 7:813–820.CrossRefPubMed

16.

• Thompson MC, Fuller C, Hogg TL, et al.: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006, 24:1924–1931. This study and the one by Kool et al. [17•] were the first to describe distinct molecular subgroups of medulloblastoma using gene expression profiling and specific genomic features for a large cohort of tumors.CrossRefPubMed

17.

• Kool M, Koster J, Bunt J, et al.: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 2008, 3:e3088. This study and the one by Thompson et al. [16•] were the first to describe distinct molecular subgroups of medulloblastoma using gene expression profiling and specific genomic features for a large cohort of tumors.CrossRefPubMed

18.

Taylor MD, Poppleton H, Fuller C, et al.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005, 8:323–3235.CrossRefPubMed

19.

Mack SC, Taylor MD: The genetic and epigenetic basis of ependymoma. Childs Nerv Syst 2009, 25:1195–1201.CrossRefPubMed

20.

• Modena P, Lualdi E, Facchinetti F, et al.: Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 2006, 24:5223–5233. Modena et al. report one of the few genome-wide copy number studies in ependymoma. This study, with a modest sample size, identified both broad and focal genetic alterations and incorporated gene expression analysis. CrossRefPubMed

21.

Mendrzyk F, Korshunov A, Benner A, et al.: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 2006, 12:2070–2079.CrossRefPubMed

22.

• Puget S, Grill J, Valent A, et al.: Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol 2009, 27:1884–1892. This study, the most recent genome-wide copy number study in ependymoma, demonstrated deregulation of several Notch family members and found several regions of genomic alteration associated with tumor recurrence.CrossRefPubMed

23.

Reddy AT, Janss AJ, Phillips PC, et al.: Outcome for children with supratentorial primitive neuroectodermal tumours treated with surgery, radiation and chemotherapy. Cancer 2000, 88:2189–2193.CrossRefPubMed

24.

Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002, 415:436–442.CrossRefPubMed

25.

Inda MM, Guilladu-Bataille M, Danglot G, et al.: Genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumours of the central nervous system. Histopathology 2005, 47:631–637.CrossRefPubMed

26.

• Pfister S, Remke M, Toedt G, et al.: Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastoma. Genes Chromosomes Cancer 2007, 46:839–851. This report on the most recent comparative genomic hybridization investigation of sPNETs highlights previous findings and describes the first identification of chromosome 17 aberrations in sPNETs.CrossRefPubMed

27.

Russo C, Pellarin M, Tingby O, et al.: Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999, 86:331–339.CrossRefPubMed

28.

McCabe MG, Ichimura K, Liu L, et al.: High-resolution array-based comparative genomic hybridization of medulloblastoma and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 2006, 65:549–561.CrossRefPubMed

29.

Kraus JA, Felsberg J, Tonn JC, et al.: Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. Neuropathol Appl Neurobiol 2002, 28:325–333.CrossRefPubMed

30.

Ohgaki H, Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005, 64:479–489.PubMed

31.

Listernick R, Ferner RE, Liu GT, Gutmann DH: Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007, 61:189–198.CrossRefPubMed

32.

Yunoue S, Tokuo H, Fukunaga K, et al.: Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem 2003, 278:26958–26969.CrossRefPubMed

33.

Sharma MK, Mansur DB, Reifenberger G, et al.: Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res 2007, 67:890–900.CrossRefPubMed

34.

Janzarik WG, Kratz CP, Loges NT, et al.: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 2007, 38:61–63.CrossRefPubMed

35.

Sharma MK, Zehnbauer BA, Watson MA, Gutmann DH: RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology 2005, 65:1335–1336.CrossRefPubMed

36.

Jones DT, Ichimura K, Liu L, et al.: Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age. J Neuropathol Exp Neurol 2006, 65:1049–1058.CrossRefPubMed

37.

Sanoudou D, Tingby O, Ferguson-Smith MA, et al.: Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br J Cancer 2000, 82:1218–1222.CrossRefPubMed

38.

Forshew T, Tatevossian RG, Lawson AR, et al.: Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 2009, 218:172–181.CrossRefPubMed

39.

Jacob K, Albrecht S, Sollier C, et al.: Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 2009, 101:722–733.CrossRefPubMed

40.

•• Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008, 118:1739–1749. This was the first study to describe BRAF duplications in more than 50% of PAs and activating BRAF mutations in nonoverlapping cases.CrossRefPubMed

41.

Bar EE, Lin A, Tihan T, et al.: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008, 67:878–887.CrossRefPubMed

42.

• Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008, 68:8673–8677. This study and the one by Sievert et al. [43•] were the first to identify BRAF fusion transcripts in PA with loss of the autoinhibitory domain.CrossRefPubMed

43.

• Sievert AJ, Jackson EM, Gai X, et al.: Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 2009, 19:449–458. This study and the one by Jones et al. [42•] were the first to identify BRAF fusion transcripts in PA with loss of the autoinhibitory domain.CrossRefPubMed

44.

Jones DT, Kocialkowski S, Liu L, et al.: Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009, 28:2119–2123.CrossRefPubMed

45.

Korshunov A, Meyer J, Capper D, et al.: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009, 118:401–405.CrossRefPubMed

46.

Brena RM, Costello JF: Genome-epigenome interactions in cancer. Rev Hum Mol Genet 2007, 16:R96–R105.CrossRef

47.

Lindsey JC, Anderton JA, Lusher ME, Clifford SC: Epigenetic events in medulloblastoma development. Neurosurg Focus 2005, 19:E10.CrossRefPubMed

48.

Anderton JA, Lindsey JC, Lusher ME, et al.: Global analysis of the medulloblastoma epigenome identifies disease subgroup-specific inactivation of COL1A2. Neuro Oncol 2008, 10:981–994.CrossRefPubMed

49.

• Kongkham P, Northcott PA, Ra YS, et al.: An epigenetic genome-wide screen identifies SPINT2 as a novel tumour suppressor gene in pediatric medulloblastoma. Cancer Res 2008, 68:9945–9953. Kongkham et al. report a novel approach integrating loss of heterozygosity and epigenetic data from pharmacologic screens to identify new pathways dysregulated in medulloblastoma.CrossRefPubMed

50.

• Pfister S, Schlaeger C, Mendrzyk F, et al.: Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma. Nucleic Acids Res 2007, 35:e51. Pfister et al. examined novel DNA hypermethylation events in primary medulloblastomas. Their report describes a clinical correlation between aberrant methylation and overall survival outcome and identifies ZIC2 as a frequent target of epigenetic silencing.CrossRefPubMed

51.

Muhlisch J, Schwering, A, Grotzer M, et al.: Epigenetic represison of RASSF1A but not CASP8 in supratentorial PNETs (sPNET) and atypical teratoid rhabdoid tumours (AT/RT) of childhood. Oncogene 2006, 25:1111–1117.CrossRefPubMed

52.

Pang JC-S, Chang Q, Chung, YF, et al.: Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumours. Hum Pathol 2005, 36:36–43.CrossRefPubMed

53.

Inda MM, Munoz J, Coullin P, et al.: High promoter hypermethylation frequency of p14/ARF in supratentorial PNET but not in medulloblastoma. Histopathology 2006, 48:579–587.CrossRefPubMed

54.

Kondo Y, Shen L, Cheng AS, et al.: Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 2008, 40:741–750.CrossRefPubMed

55.

Pfister S, Witt O: Pediatric gliomas. Recent Results Cancer Res 2009, 171:67–81.CrossRefPubMed

Title: The Genetics of Pediatric Brain Tumors
Authors: Adrian M. Dubuc
Paul A. Northcott
Stephen Mack
Hendrik Witt
Stefan Pfister
Michael D. Taylor
Publication date: 01-05-2010
Publisher: Current Science Inc.
Published in: Current Neurology and Neuroscience Reports / Issue 3/2010
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-010-0103-9

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The Genetics of Pediatric Brain Tumors

Abstract

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