Key Points
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Medulloblastoma is a malignant brain tumour that occurs predominantly in childhood, but is also seen in infancy and throughout adulthood
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Although the prognosis of medulloblastoma is favourable with current therapeutic regimens, the heterogeneous nature of this cancer has confounded efforts to substantially improve survival and reduce therapy-related toxicity
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Advancements in technology and its accessibility have led, through molecular interrogation, to the recognition that medulloblastoma heterogeneity is broadly explained by the existence of four main molecular tumour subtypes
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Each molecular medulloblastoma subtype, termed Wnt, SHH, group 3, and group 4 medulloblastoma, has unique clinical and molecular characteristics, which influence nearly every facet of the disease, including survival
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Armed with this knowledge, paediatric oncologists find themselves at an opportune moment to capitalize on these newly elucidated characteristics to improve survival and reduce morbidity by tailoring therapy towards the individual subtypes
Abstract
Medulloblastoma is a form of brain cancer that mainly arises during infancy and childhood. Our understanding of this disease has transitioned rapidly; what was once thought of as a single disease entity is now known to be a compendium comprising at least four distinct subtypes of tumour (Wnt, sonic hedgehog [SHH], group 3, and group 4 medulloblastomas) that have characteristic molecular signatures, distinctive clinical features, and are associated with different outcomes. Importantly, medulloblastomas occurring in infants (aged up to 3 years) and adults have unique characteristics, which distinguish the disease from that seen in children aged >3 years. Accordingly, modern treatment approaches in medulloblastoma integrate the molecular and clinical features of the disease to enable provision of the most-effective therapies for each patient, and to reduce long-term sequelae. This Review discusses our current knowledge of medulloblastoma. In particular, we present the genetic and histological features, patient demographics, prognosis, and therapeutic options for each the four molecular tumour subtypes that comprise this disease entity. In addition, the unique features of medulloblastoma in infants and in adults, as compared with childhood and/or adolescent forms, are described.
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References
Pui, C. H., Gajjar, A. J., Kane, J. R., Qaddoumi, I. A. & Pappo, A. S. Challenging issues in pediatric oncology. Nat. Rev. Clin. Oncol. 8, 540–549 (2011).
Packer, R. J. et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 24, 4202–4208 (2006).
Gajjar, A. 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. 7, 813–820 (2006).
Rutkowski, S. et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N. Engl. J. Med. 352, 978–986 (2005).
Ellison, D. W. et al. β-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J. Clin. Oncol. 23, 7951–7957 (2005).
Packer, R. J. et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children's Cancer Group Study. J. Clin. Oncol. 17, 2127–2136 (1999).
Silber, J. H. et al. Whole-brain irradiation and decline in intelligence: the influence of dose and age on IQ score. J. Clin. Oncol. 10, 1390–1396 (1992).
Mulhern, R. K., Merchant, T. E., Gajjar, A. Reddick, W. E. & Kun, L. E. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. 5, 399–408 (2004).
Hoppe-Hirsch, E. et al. Medulloblastoma in childhood: progressive intellectual deterioration. Childs Nerv. Syst. 6, 60–65 (1990).
Laughton, S. J. et al. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J. Clin. Oncol. 26, 1112–1118 (2008).
Wolfe, K. R. et al. Cardiorespiratory fitness in survivors of pediatric posterior fossa tumor. J. Pediatr. Hematol. Oncol. 34, e222–e227 (2012).
Ness, K. K., Wall, M. M., Oakes, J. M., Robison, L. L. & Gurney, J. G. Physical performance limitations and participation restrictions among cancer survivors: a population-based study. Ann. Epidemiol. 16, 197–205 (2006).
Armstrong, G. T. et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J. Natl Cancer Inst. 101, 946–958 (2009).
Mabbott, D. J. et al. Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J. Clin. Oncol. 23, 2256–2263 (2005).
Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).
Cho, Y. J. et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424–1430 (2011).
Kool, M. 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. Acta Neuropathol. 123, 473–484 (2012).
Louis, D. N. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).
Eberhart, C. G. et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 94, 552–560 (2002).
Ellison, D. W. Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease. Acta Neuropathol. 120, 305–316 (2010).
Ellison, D. W. et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J. Clin. Oncol. 29, 1400–1407 (2011).
McManamy, C. S. et al. Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J. Neuropathol. Exp. Neurol. 62, 627–632 (2003).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
Thompson, M. C. et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J. Clin. Oncol. 24, 1924–1931 (2006).
Northcott, P. A. et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 1408–1414 (2011).
Kool, M. et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 3, e3088 (2008).
Taylor, M. D. et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123, 465–472 (2012).
Clifford, S. C. 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 5, 2666–2670 (2006).
Ellison, D. W. et al. Medulloblastoma: clinicopathological correlates of, SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 121, 381–396 (2011).
Northcott, P. A. et al. Medulloblastomics: the end of the beginning. Nat. Rev. Cancer 12, 818–834 (2012).
Northcott, P. A., Korshunov, A., Pfister, S. M. & Taylor, M. D. The clinical implications of medulloblastoma subgroups. Nat. Rev. Neurol. 8, 340–351 (2012).
Mosimann, C., Hausmann, G. & Basler, K. β-catenin hits chromatin: regulation of Wnt target gene activation. Nat. Rev. Mol. Cell Biol. 10, 276–286 (2009).
Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012).
Jones, D. T. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012).
Pugh, T. J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).
Gilbertson, R. J. Medulloblastoma: signalling a change in treatment. Lancet Oncol. 5, 209–218 (2004).
Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).
Fujii, K. & Miyashita, T. Gorlin syndrome (nevoid basal cell carcinoma syndrome)—an update and literature review. Pediatr. Int. http://dx.doi.org/10.1111/ped.12461.
Huangfu, D. & Anderson, K. V. Signaling from Smo to Ci/Gli: conservation and diveregence of Hedgehog pathways from Drosophilia to vertebrates. Development 133, 3–14 (2006).
Goodrich, L. V., Milenkovic´, L. Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).
Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25, 393–405 (2014).
Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 31, 306–310 (2002).
Northcott, P. A. et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012).
Shih, D. J. et al. Cytogenetic prognostication within medulloblastoma subgroups. J. Clin. Oncol. 32, 886–896 (2014).
Grammel, D. et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 123, 601–614 (2012).
Northcott, P. A. et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 122, 231–240 (2011).
Rudin, C. M. et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173–1178 (2009).
Metcalfe, C. & de Sauvage, F. J. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 71, 5057–5061 (2011).
Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572–574 (2009).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
Northcott, P. A. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014).
Kawauchi, D. et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell 21, 168–180 (2012).
Pei, Y. et al. An animal model of MYC-driven medulloblastoma. Cancer Cell 21, 155–167 (2012).
Morfouace, M. et al. Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 25, 516–529 (2014).
Bandopadhayay, P. et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin. Cancer Res. 20, 912–925 (2014).
Rutkowski. S. et al. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J. Clin. Oncol. 28, 4961–4968 (2010).
Ashley, D. M. et al. Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children's Oncology Group study P9934. J. Clin. Oncol. 30, 3181–3186 (2012).
Chi, S. N. et al. Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J. Clin. Oncol. 22, 4881–4887 (2004).
Kool, M., Korshunov, A. & Pfister, S. M. Update on molecular and genetic alterations in adult medulloblastoma. Memo 5, 228–232 (2012).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
Acknowledgements
The work of the authors is supported, in part, by Cancer Centre CORE Grant CA 21765, the Noyes Brain Tumour Foundation, Musicians Against Childhood Cancer (MACC), and the American Lebanese Syrian Associated Charities (ALSAC).
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Both authors researched the data, contributed to discussions of content, wrote the article, and reviewed/edited the manuscript before submission.
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A.J.G. and G.W.R. are investigators on a clinical protocol that is funded, in part, by Genentech.
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Gajjar, A., Robinson, G. Medulloblastoma—translating discoveries from the bench to the bedside. Nat Rev Clin Oncol 11, 714–722 (2014). https://doi.org/10.1038/nrclinonc.2014.181
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DOI: https://doi.org/10.1038/nrclinonc.2014.181
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