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Published in: Acta Neuropathologica 3/2010

01-09-2010 | Review

Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease

Author: David W. Ellison

Published in: Acta Neuropathologica | Issue 3/2010

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Abstract

Increasing recognition of pediatric medulloblastoma as a heterogeneous disease, with histopathological and molecular variants that have distinct biological behaviors, will impact how the disease is classified and treated. A combination of clinicopathological evaluation and assays based on molecular subgroups of disease will allow stratification of patients into risk groups and a more tailored approach to therapy. Patients with low-risk disease could be treated with de-escalated adjuvant therapy to maximize cure while reducing long-term adverse effects, and novel therapies could be sought for patients with high-risk disease. My review encompasses a brief overview of the clinical landscape, the current World Health Organization (WHO) classification of medulloblastoma, the status of molecular subgroups, and how potential stratification schemes might impact pathologists and their practice.
Literature
1.
go back to reference Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med 126:540–544PubMed Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med 126:540–544PubMed
2.
go back to reference Aldosari N, Rasheed BK, McLendon RE, Friedman HS, Bigner DD, Bigner SH (2000) Characterization of chromosome 17 abnormalities in medulloblastomas. Acta Neuropathol 99:345–351CrossRefPubMed Aldosari N, Rasheed BK, McLendon RE, Friedman HS, Bigner DD, Bigner SH (2000) Characterization of chromosome 17 abnormalities in medulloblastomas. Acta Neuropathol 99:345–351CrossRefPubMed
3.
go back to reference Ayrault O, Zhao H, Zindy F, Qu C, Sherr CJ, Roussel MF (2010) Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells. Cancer Res 70:5618–5627CrossRefPubMed Ayrault O, Zhao H, Zindy F, Qu C, Sherr CJ, Roussel MF (2010) Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells. Cancer Res 70:5618–5627CrossRefPubMed
4.
go back to reference Badiali M, Pession A, Basso G, Andreini L, Rigobello L, Galassi E, Giangaspero F (1991) N-myc and c-myc oncogenes amplification in medulloblastomas. Evidence of particularly aggressive behavior of a tumor with c-myc amplification. Tumori 77:118–121PubMed Badiali M, Pession A, Basso G, Andreini L, Rigobello L, Galassi E, Giangaspero F (1991) N-myc and c-myc oncogenes amplification in medulloblastomas. Evidence of particularly aggressive behavior of a tumor with c-myc amplification. Tumori 77:118–121PubMed
5.
go back to reference Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, Phillips PC (1997) Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 3:473–478PubMed Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, Phillips PC (1997) Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res 3:473–478PubMed
6.
go back to reference Biegel JA, Rorke LB, Janss AJ, Sutton LN, Parmiter AH (1995) Isochromosome 17q demonstrated by interphase fluorescence in situ hybridization in primitive neuroectodermal tumors of the central nervous system. Genes Chromosomes Cancer 14:85–96CrossRefPubMed Biegel JA, Rorke LB, Janss AJ, Sutton LN, Parmiter AH (1995) Isochromosome 17q demonstrated by interphase fluorescence in situ hybridization in primitive neuroectodermal tumors of the central nervous system. Genes Chromosomes Cancer 14:85–96CrossRefPubMed
7.
go back to reference Biegel JA, Rorke LB, Packer RJ, Sutton LN, Schut L, Bonner K, Emanuel BS (1989) Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system. Genes Chromosomes Cancer 1:139–147CrossRefPubMed Biegel JA, Rorke LB, Packer RJ, Sutton LN, Schut L, Bonner K, Emanuel BS (1989) Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system. Genes Chromosomes Cancer 1:139–147CrossRefPubMed
8.
go back to reference Bouffet E (2010) Medulloblastoma in infants: the critical issues of the dilemma. Curr Oncol 17:2–3PubMed Bouffet E (2010) Medulloblastoma in infants: the critical issues of the dilemma. Curr Oncol 17:2–3PubMed
9.
go back to reference Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865PubMed Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865PubMed
10.
go back to reference Buhren J, Christoph AH, Buslei R, Albrecht S, Wiestler OD, Pietsch T (2000) Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features: evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol 59:229–240PubMed Buhren J, Christoph AH, Buslei R, Albrecht S, Wiestler OD, Pietsch T (2000) Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features: evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol 59:229–240PubMed
11.
go back to reference Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW (2006) Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 5:2666–2670PubMed Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW (2006) Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 5:2666–2670PubMed
12.
go back to reference Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T (2001) Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 61:7039–7043PubMed Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T (2001) Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 61:7039–7043PubMed
13.
14.
go back to reference Eberhart CG, Kaufman WE, Tihan T, Burger PC (2001) Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules. J Neuropathol Exp Neurol 60:462–469PubMed Eberhart CG, Kaufman WE, Tihan T, Burger PC (2001) Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules. J Neuropathol Exp Neurol 60:462–469PubMed
15.
go back to reference Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 94:552–560CrossRefPubMed Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 94:552–560CrossRefPubMed
16.
go back to reference Eberhart CG, Tihan T, Burger PC (2000) Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 59:333–337PubMed Eberhart CG, Tihan T, Burger PC (2000) Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 59:333–337PubMed
17.
go back to reference Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28:257–282CrossRefPubMed Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28:257–282CrossRefPubMed
18.
go back to reference Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ (2003) What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53–66CrossRefPubMed Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ (2003) What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53–66CrossRefPubMed
19.
go back to reference Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC (2005) beta-Catenin status predicts a favorable outcome in childhood medulloblastoma. J Clin Oncol 23:7951–7957CrossRefPubMed Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC (2005) beta-Catenin status predicts a favorable outcome in childhood medulloblastoma. J Clin Oncol 23:7951–7957CrossRefPubMed
20.
go back to reference Emmenegger BA, Wechsler-Reya RJ (2008) Stem cells and the origin and propagation of brain tumors. J Child Neurol 23:1172–1178CrossRefPubMed Emmenegger BA, Wechsler-Reya RJ (2008) Stem cells and the origin and propagation of brain tumors. J Child Neurol 23:1172–1178CrossRefPubMed
21.
go back to reference Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (1991) The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64:959–961PubMed Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (1991) The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64:959–961PubMed
22.
go back to reference Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, Delattre O (2009) Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. J Pathol 218:86–94CrossRefPubMed Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, Delattre O (2009) Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. J Pathol 218:86–94CrossRefPubMed
23.
go back to reference Frange P, Alapetite C, Gaboriaud G, Bours D, Zucker JM, Zerah M, Brisse H, Chevignard M, Mosseri V, Bouffet E, Doz F (2009) From childhood to adulthood: long-term outcome of medulloblastoma patients. The Institut Curie experience (1980–2000). J Neurooncol 95:271–279CrossRefPubMed Frange P, Alapetite C, Gaboriaud G, Bours D, Zucker JM, Zerah M, Brisse H, Chevignard M, Mosseri V, Bouffet E, Doz F (2009) From childhood to adulthood: long-term outcome of medulloblastoma patients. The Institut Curie experience (1980–2000). J Neurooncol 95:271–279CrossRefPubMed
24.
go back to reference Frappart PO, Lee Y, Lamont J, McKinnon PJ (2007) BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J 26:2732–2742CrossRefPubMed Frappart PO, Lee Y, Lamont J, McKinnon PJ (2007) BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J 26:2732–2742CrossRefPubMed
25.
26.
go back to reference Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ (2006) 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 7:813–820CrossRefPubMed Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ (2006) 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 7:813–820CrossRefPubMed
27.
go back to reference Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM, Kellie SJ, Kun L, Gilbertson RJ (2004) Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984–993CrossRefPubMed Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM, Kellie SJ, Kun L, Gilbertson RJ (2004) Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984–993CrossRefPubMed
28.
go back to reference Gajjar A, Mulhern RK, Heideman RL, Sanford RA, Douglass EC, Kovnar EH, Langston JA, Jenkins JJ, Kun LE (1994) Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy. J Clin Oncol 12:1212–1216PubMed Gajjar A, Mulhern RK, Heideman RL, Sanford RA, Douglass EC, Kovnar EH, Langston JA, Jenkins JJ, Kun LE (1994) Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy. J Clin Oncol 12:1212–1216PubMed
29.
go back to reference Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, Burger PC, Garre ML (1999) Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91:971–977CrossRefPubMed Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, Burger PC, Garre ML (1999) Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91:971–977CrossRefPubMed
30.
go back to reference Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, Zorzi F, Montaldi A (1992) Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 16:687–693CrossRefPubMed Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, Zorzi F, Montaldi A (1992) Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 16:687–693CrossRefPubMed
31.
go back to reference Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry R, Lunec J, Pearson A, Ellison D (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712CrossRefPubMed Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry R, Lunec J, Pearson A, Ellison D (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712CrossRefPubMed
32.
33.
go back to reference Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annu Rev Pathol 3:341–365CrossRefPubMed Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annu Rev Pathol 3:341–365CrossRefPubMed
34.
go back to reference Gilbertson RJ, Gajjar A (2005) Molecular biology of medulloblastoma: will it ever make a difference to clinical management? J Neurooncol 75:273–278CrossRefPubMed Gilbertson RJ, Gajjar A (2005) Molecular biology of medulloblastoma: will it ever make a difference to clinical management? J Neurooncol 75:273–278CrossRefPubMed
35.
go back to reference Giordana MT, D’Agostino C, Pollo B, Silvani A, Ferracini R, Paiolo A, Ghiglione P, Chio A (2005) Anaplasia is rare and does not influence prognosis in adult medulloblastoma. J Neuropathol Exp Neurol 64:869–874CrossRefPubMed Giordana MT, D’Agostino C, Pollo B, Silvani A, Ferracini R, Paiolo A, Ghiglione P, Chio A (2005) Anaplasia is rare and does not influence prognosis in adult medulloblastoma. J Neuropathol Exp Neurol 64:869–874CrossRefPubMed
36.
go back to reference Gottardo NG, Gajjar A (2006) Current Therapy for Medulloblastoma. Curr Treat Options Neurol 8:319–334CrossRefPubMed Gottardo NG, Gajjar A (2006) Current Therapy for Medulloblastoma. Curr Treat Options Neurol 8:319–334CrossRefPubMed
37.
go back to reference Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI, Chastagner P, Couanet D, Habrand JL, Raquin MA, Le Deley MC, Kalifa C (2005) Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6:573–580CrossRefPubMed Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI, Chastagner P, Couanet D, Habrand JL, Raquin MA, Le Deley MC, Kalifa C (2005) Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6:573–580CrossRefPubMed
38.
go back to reference Grundy RG, Wilne SH, Robinson KJ, Ironside JW, Cox T, Chong WK, Michalski A, Campbell RH, Bailey CC, Thorp N, Pizer B, Punt J, Walker DA, Ellison DW, Machin D (2010) Primary postoperative chemotherapy without radiotherapy for treatment of brain tumors other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 46:120–133CrossRefPubMed Grundy RG, Wilne SH, Robinson KJ, Ironside JW, Cox T, Chong WK, Michalski A, Campbell RH, Bailey CC, Thorp N, Pizer B, Punt J, Walker DA, Ellison DW, Machin D (2010) Primary postoperative chemotherapy without radiotherapy for treatment of brain tumors other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 46:120–133CrossRefPubMed
39.
go back to reference Gulino A, Arcella A, Giangaspero F (2008) Pathological and molecular heterogeneity of medulloblastoma. Curr Opin Oncol 20:668–675CrossRefPubMed Gulino A, Arcella A, Giangaspero F (2008) Pathological and molecular heterogeneity of medulloblastoma. Curr Opin Oncol 20:668–675CrossRefPubMed
40.
go back to reference Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA, Olson JM (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800CrossRefPubMed Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA, Olson JM (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800CrossRefPubMed
41.
go back to reference Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B, Hansen S, Knoblaugh SE, Lee D, Eberhart CG, Hallahan AR, Olson JM (2008) The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 68:1768–1776CrossRefPubMed Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B, Hansen S, Knoblaugh SE, Lee D, Eberhart CG, Hallahan AR, Olson JM (2008) The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 68:1768–1776CrossRefPubMed
42.
go back to reference Henderson BR, Fagotto F (2002) The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep 3:834–839CrossRefPubMed Henderson BR, Fagotto F (2002) The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep 3:834–839CrossRefPubMed
43.
go back to reference Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H (2000) APC mutations in sporadic medulloblastomas. Am J Pathol 156:433–437PubMed Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H (2000) APC mutations in sporadic medulloblastomas. Am J Pathol 156:433–437PubMed
44.
go back to reference Kimura H, Ng JM, Curran T (2008) Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13:249–260CrossRefPubMed Kimura H, Ng JM, Curran T (2008) Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13:249–260CrossRefPubMed
45.
go back to reference Koch A, Hrychyk A, Hartmann W, Waha A, Mikeska T, Schuller U, Sorensen N, Berthold F, Goodyer CG, Wiestler OD, Birchmeier W, Behrens J, Pietsch T (2007) Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. Int J Cancer 121:284–291CrossRefPubMed Koch A, Hrychyk A, Hartmann W, Waha A, Mikeska T, Schuller U, Sorensen N, Berthold F, Goodyer CG, Wiestler OD, Birchmeier W, Behrens J, Pietsch T (2007) Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. Int J Cancer 121:284–291CrossRefPubMed
46.
go back to reference Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G, Wiestler OD, Pietsch T (2001) Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445–449CrossRefPubMed Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G, Wiestler OD, Pietsch T (2001) Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445–449CrossRefPubMed
47.
go back to reference Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, Mrsic A, Ylstra B, Grajkowska W, Hartmann W, Pietsch T, Ellison D, Clifford SC, Versteeg R (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3:e3088CrossRefPubMed Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, Mrsic A, Ylstra B, Grajkowska W, Hartmann W, Pietsch T, Ellison D, Clifford SC, Versteeg R (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3:e3088CrossRefPubMed
48.
go back to reference Kun LE, Mulhern RK, Crisco JJ (1983) Quality of life in children treated for brain tumors. Intellectual, emotional, and academic function. J Neurosurg 58:1–6CrossRefPubMed Kun LE, Mulhern RK, Crisco JJ (1983) Quality of life in children treated for brain tumors. Intellectual, emotional, and academic function. J Neurosurg 58:1–6CrossRefPubMed
49.
go back to reference Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW (2004) Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10:5482–5493CrossRefPubMed Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW (2004) Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10:5482–5493CrossRefPubMed
50.
go back to reference Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447CrossRefPubMed Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447CrossRefPubMed
51.
go back to reference Louis DN (2007) WHO classification of tumors of the central nervous system. International Agency for Research on Cancer, Lyon Louis DN (2007) WHO classification of tumors of the central nervous system. International Agency for Research on Cancer, Lyon
52.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMed Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMed
53.
go back to reference Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11:17–22CrossRefPubMed Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11:17–22CrossRefPubMed
54.
go back to reference McCabe MG, Ichimura K, Liu L, Plant K, Backlund LM, Pearson DM, Collins VP (2006) High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 65:549–561CrossRefPubMed McCabe MG, Ichimura K, Liu L, Plant K, Backlund LM, Pearson DM, Collins VP (2006) High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 65:549–561CrossRefPubMed
55.
go back to reference McManamy CS, Lamont JM, Taylor RE, Cole M, Pearson AD, Clifford SC, Ellison DW (2003) Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:627–632PubMed McManamy CS, Lamont JM, Taylor RE, Cole M, Pearson AD, Clifford SC, Ellison DW (2003) Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:627–632PubMed
56.
go back to reference McManamy CS, Pears J, Weston CL, Hanzely Z, Ironside JW, Taylor RE, Grundy RG, Clifford SC, Ellison DW (2007) Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17:151–164CrossRefPubMed McManamy CS, Pears J, Weston CL, Hanzely Z, Ironside JW, Taylor RE, Grundy RG, Clifford SC, Ellison DW (2007) Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17:151–164CrossRefPubMed
57.
go back to reference Merchant TE, Kun LE, Krasin MJ, Wallace D, Chintagumpala MM, Woo SY, Ashley DM, Sexton M, Kellie SJ, Ahern V, Gajjar A (2008) Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 70:782–787PubMed Merchant TE, Kun LE, Krasin MJ, Wallace D, Chintagumpala MM, Woo SY, Ashley DM, Sexton M, Kellie SJ, Ahern V, Gajjar A (2008) Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 70:782–787PubMed
58.
go back to reference Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE (2004) Late neurocognitive sequelae in survivors of brain tumors in childhood. Lancet Oncol 5:399–408CrossRefPubMed Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE (2004) Late neurocognitive sequelae in survivors of brain tumors in childhood. Lancet Oncol 5:399–408CrossRefPubMed
59.
go back to reference Nicholson J, Wickramasinghe C, Ross F, Crolla J, Ellison D (2000) Imbalances of chromosome 17 in medulloblastomas determined by comparative genomic hybridisation and fluorescence in situ hybridisation. Mol Pathol 53:313–319CrossRefPubMed Nicholson J, Wickramasinghe C, Ross F, Crolla J, Ellison D (2000) Imbalances of chromosome 17 in medulloblastomas determined by comparative genomic hybridisation and fluorescence in situ hybridisation. Mol Pathol 53:313–319CrossRefPubMed
60.
go back to reference Nicholson JC, Ross FM, Kohler JA, Ellison DW (1999) Comparative genomic hybridization and histological variation in primitive neuroectodermal tumors. Br J Cancer 80:1322–1331CrossRefPubMed Nicholson JC, Ross FM, Kohler JA, Ellison DW (1999) Comparative genomic hybridization and histological variation in primitive neuroectodermal tumors. Br J Cancer 80:1322–1331CrossRefPubMed
61.
go back to reference Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2010) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol (in press) Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2010) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol (in press)
62.
go back to reference Oyharcabal-Bourden V, Kalifa C, Gentet JC, Frappaz D, Edan C, Chastagner P, Sariban E, Pagnier A, Babin A, Pichon F, Neuenschwander S, Vinchon M, Bours D, Mosseri V, Le Gales C, Ruchoux M, Carrie C, Doz F (2005) Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23:4726–4734CrossRefPubMed Oyharcabal-Bourden V, Kalifa C, Gentet JC, Frappaz D, Edan C, Chastagner P, Sariban E, Pagnier A, Babin A, Pichon F, Neuenschwander S, Vinchon M, Bours D, Mosseri V, Le Gales C, Ruchoux M, Carrie C, Doz F (2005) Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23:4726–4734CrossRefPubMed
63.
go back to reference Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208CrossRefPubMed Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208CrossRefPubMed
64.
go back to reference Packer RJ, Vezina G (2008) Management of and prognosis with medulloblastoma: therapy at a crossroads. Arch Neurol 65:1419–1424CrossRefPubMed Packer RJ, Vezina G (2008) Management of and prognosis with medulloblastoma: therapy at a crossroads. Arch Neurol 65:1419–1424CrossRefPubMed
65.
go back to reference Pan E, Pellarin M, Holmes E, Smirnov I, Misra A, Eberhart CG, Burger PC, Biegel JA, Feuerstein BG (2005) Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 11:4733–4740CrossRefPubMed Pan E, Pellarin M, Holmes E, Smirnov I, Misra A, Eberhart CG, Burger PC, Biegel JA, Feuerstein BG (2005) Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 11:4733–4740CrossRefPubMed
66.
go back to reference Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A (2009) 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 27:1627–1636CrossRefPubMed Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A (2009) 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 27:1627–1636CrossRefPubMed
67.
go back to reference Piedimonte LR, Wailes IK, Weiner HL (2005) Medulloblastoma: mouse models and novel targeted therapies based on the Sonic hedgehog pathway. Neurosurg Focus 19:E8CrossRefPubMed Piedimonte LR, Wailes IK, Weiner HL (2005) Medulloblastoma: mouse models and novel targeted therapies based on the Sonic hedgehog pathway. Neurosurg Focus 19:E8CrossRefPubMed
68.
go back to reference Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wiestler OD, Wicking C (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088PubMed Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wiestler OD, Wicking C (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088PubMed
69.
go back to reference Pizer BL, Clifford SC (2009) The potential impact of tumor biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg 23:364–375CrossRefPubMed Pizer BL, Clifford SC (2009) The potential impact of tumor biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg 23:364–375CrossRefPubMed
70.
go back to reference Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES, Golub TR (2002) Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature 415:436–442CrossRefPubMed Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES, Golub TR (2002) Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature 415:436–442CrossRefPubMed
71.
go back to reference Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845PubMed Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845PubMed
72.
go back to reference Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G (1998) Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58:1798–1803PubMed Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G (1998) Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58:1798–1803PubMed
73.
go back to reference Romer J, Curran T (2005) Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 65:4975–4978CrossRefPubMed Romer J, Curran T (2005) Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 65:4975–4978CrossRefPubMed
74.
go back to reference Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H, Connelly M, Stewart CF, Gould S, Rubin LL, Curran T (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(±)p53(−/−) mice. Cancer Cell 6:229–240CrossRefPubMed Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H, Connelly M, Stewart CF, Gould S, Rubin LL, Curran T (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(±)p53(−/−) mice. Cancer Cell 6:229–240CrossRefPubMed
75.
go back to reference Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178CrossRefPubMed Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178CrossRefPubMed
76.
go back to reference Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986CrossRefPubMed Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986CrossRefPubMed
77.
go back to reference Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N, Berthold F, Henze G, Wolff JE, Warmuth-Metz M, Soerensen N, Emser A, Ottensmeier H, Deinlein F, Schlegel PG, Kortmann RD, Pietsch T, Kuehl J (2009) Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11:201–210CrossRefPubMed Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N, Berthold F, Henze G, Wolff JE, Warmuth-Metz M, Soerensen N, Emser A, Ottensmeier H, Deinlein F, Schlegel PG, Kortmann RD, Pietsch T, Kuehl J (2009) Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11:201–210CrossRefPubMed
78.
go back to reference Rutkowski S, von Bueren A, von Hoff K, Hartmann W, Shalaby T, Deinlein F, Warmuth-Metz M, Soerensen N, Emser A, Bode U, Mittler U, Urban C, Benesch M, Kortmann RD, Schlegel PG, Kuehl J, Pietsch T, Grotzer M (2007) Prognostic relevance of clinical and biological risk factors in childhood medulloblastoma: results of patients treated in the prospective multicenter trial HIT’91. Clin Cancer Res 13:2651–2657CrossRefPubMed Rutkowski S, von Bueren A, von Hoff K, Hartmann W, Shalaby T, Deinlein F, Warmuth-Metz M, Soerensen N, Emser A, Bode U, Mittler U, Urban C, Benesch M, Kortmann RD, Schlegel PG, Kuehl J, Pietsch T, Grotzer M (2007) Prognostic relevance of clinical and biological risk factors in childhood medulloblastoma: results of patients treated in the prospective multicenter trial HIT’91. Clin Cancer Res 13:2651–2657CrossRefPubMed
79.
go back to reference Stearns D, Chaudhry A, Abel TW, Burger PC, Dang CV, Eberhart CG (2006) c-myc overexpression causes anaplasia in medulloblastoma. Cancer Res 66:673–681CrossRefPubMed Stearns D, Chaudhry A, Abel TW, Burger PC, Dang CV, Eberhart CG (2006) c-myc overexpression causes anaplasia in medulloblastoma. Cancer Res 66:673–681CrossRefPubMed
80.
go back to reference Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28:1345–1350CrossRefPubMed Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28:1345–1350CrossRefPubMed
81.
go back to reference Taniguchi E, Cho MJ, Arenkiel BR, Hansen MS, Rivera OJ, McCleish AT, Qualman SJ, Guttridge DC, Scott MP, Capecchi MR, Keller C (2009) Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma. Pediatr Blood Cancer 53:136–144CrossRefPubMed Taniguchi E, Cho MJ, Arenkiel BR, Hansen MS, Rivera OJ, McCleish AT, Qualman SJ, Guttridge DC, Scott MP, Capecchi MR, Keller C (2009) Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma. Pediatr Blood Cancer 53:136–144CrossRefPubMed
82.
go back to reference Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310CrossRefPubMed Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310CrossRefPubMed
83.
go back to reference Taylor MD, Mainprize TG, Rutka JT (2000) Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 47:888–901CrossRefPubMed Taylor MD, Mainprize TG, Rutka JT (2000) Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 47:888–901CrossRefPubMed
84.
go back to reference Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, Lucraft H, Gilbertson R, Tait DM, Walker DA, Pizer BL, Imeson J, Lashford LS (2003) Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study. J Clin Oncol 21:1581–1591CrossRefPubMed Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, Lucraft H, Gilbertson R, Tait DM, Walker DA, Pizer BL, Imeson J, Lashford LS (2003) Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study. J Clin Oncol 21:1581–1591CrossRefPubMed
85.
go back to reference Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS (2005) Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727–734CrossRefPubMed Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS (2005) Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727–734CrossRefPubMed
86.
go back to reference Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931CrossRefPubMed Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931CrossRefPubMed
87.
go back to reference Uziel T, Karginov FV, Xie S, Parker JS, Wang YD, Gajjar A, He L, Ellison D, Gilbertson RJ, Hannon G, Roussel MF (2009) The miR-17 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci USA 106:2812–2817CrossRefPubMed Uziel T, Karginov FV, Xie S, Parker JS, Wang YD, Gajjar A, He L, Ellison D, Gilbertson RJ, Hannon G, Roussel MF (2009) The miR-17 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci USA 106:2812–2817CrossRefPubMed
88.
go back to reference Uziel T, Zindy F, Xie S, Lee Y, Forget A, Magdaleno S, Rehg JE, Calabrese C, Solecki D, Eberhart CG, Sherr SE, Plimmer S, Clifford SC, Hatten ME, McKinnon PJ, Gilbertson RJ, Curran T, Sherr CJ, Roussel MF (2005) The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Genes Dev 19:2656–2667CrossRefPubMed Uziel T, Zindy F, Xie S, Lee Y, Forget A, Magdaleno S, Rehg JE, Calabrese C, Solecki D, Eberhart CG, Sherr SE, Plimmer S, Clifford SC, Hatten ME, McKinnon PJ, Gilbertson RJ, Curran T, Sherr CJ, Roussel MF (2005) The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Genes Dev 19:2656–2667CrossRefPubMed
89.
go back to reference Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R (1997) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumors. Oncogene 15:361–366CrossRefPubMed Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R (1997) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumors. Oncogene 15:361–366CrossRefPubMed
90.
go back to reference Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516PubMed Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516PubMed
91.
go back to reference Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH, Wainwright BJ, Wechsler-Reya RJ (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145CrossRefPubMed Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH, Wainwright BJ, Wechsler-Reya RJ (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145CrossRefPubMed
92.
go back to reference Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574CrossRefPubMed Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574CrossRefPubMed
93.
go back to reference Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845PubMed Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845PubMed
94.
go back to reference Zindy F, Nilsson LM, Nguyen L, Meunier C, Smeyne RJ, Rehg JE, Eberhart C, Sherr CJ, Roussel MF (2003) Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. Cancer Res 63:5420–5427PubMed Zindy F, Nilsson LM, Nguyen L, Meunier C, Smeyne RJ, Rehg JE, Eberhart C, Sherr CJ, Roussel MF (2003) Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. Cancer Res 63:5420–5427PubMed
95.
go back to reference Zurawel RH, Chiappa SA, Allen C, Raffel C (1998) Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 58:896–899PubMed Zurawel RH, Chiappa SA, Allen C, Raffel C (1998) Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 58:896–899PubMed
Metadata
Title
Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease
Author
David W. Ellison
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 3/2010
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-010-0726-6

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