Advertisement

Genetic Basis and Classification of Cerebral Neoplasms

  • Vijay Ramaswamy
  • Carolina Nör
Living reference work entry

Abstract

Historically cerebral neoplasms have been classified based on their morphological appearance. However, over the past one to two decades, there has been an explosion in our knowledge of cerebral neoplasms in childhood. This advancement in knowledge has primarily been a result of the advent of integrated genomics and next-generation sequencing. This has resulted in tremendous new insights into both the germline and somatic events underlying the pathogenesis of cerebral neoplasms. These insights provide the basis for the next generation of molecular classification of pediatric brain tumors, which provides more accurate diagnoses and more robust risk stratifications. Furthermore, targeted therapies and more personalized medicine are on the forefront of current and future clinical trials as a result of the identification of targetable events and development of new classes of agents. Advances in our understanding of the biology of pediatric brain tumors are proceeding at a very rapid pace, whereby the major challenge facing clinicians is determining how to translate this knowledge. These advances have allowed a deeper understanding of known familial syndromes, in addition to the identification of new syndromes paving the way to more comprehensive screening protocols aimed at early detection of neoplasms. The introduction of next-generation sequencing and advanced genomic methods into the clinic is an ongoing process, and future clinical trials and risk stratification schemes will undoubtedly incorporate molecular approaches.

References

  1. Ater JL, Xia C, Mazewski CM, Booth TN, Freyer DR, Packer RJ, Sposto R, Vezina G, Pollack IF (2016) Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children’s Oncology Group. Cancer 122:1928–1936CrossRefGoogle Scholar
  2. Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V et al (2016) Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34:2206–2211CrossRefGoogle Scholar
  3. Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L et al (2014) Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 46:161–165CrossRefGoogle Scholar
  4. Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, De Jay N, Ramkissoon LA et al (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462–466CrossRefGoogle Scholar
  5. Garre ML, Cama A, Bagnasco F, Morana G, Giangaspero F, Brisigotti M, Gambini C, Forni M, Rossi A, Haupt R et al (2009) Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome – a new clinical perspective. Clin Cancer Res 15:2463–2471CrossRefGoogle Scholar
  6. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J et al (2010) Subtypes of medulloblastoma have distinct developmental origins. Nature 468:1095–1099CrossRefGoogle Scholar
  7. Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo PJ et al (2015) Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21:827CrossRefGoogle Scholar
  8. Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, Fang D, Huang X, Tom MW, Ngo V et al (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394–1396CrossRefGoogle Scholar
  9. Hasselblatt M, Nagel I, Oyen F, Bartelheim K, Russell RB, Schuller U, Junckerstorff R, Rosenblum M, Alassiri AH, Rossi S et al (2014) SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128:453–456CrossRefGoogle Scholar
  10. Herrlinger U, Jones DT, Glas M, Hattingen E, Gramatzki D, Stuplich M, Felsberg J, Bahr O, Gielen GH, Simon M et al (2016) Gliomatosis cerebri: no evidence for a separate brain tumor entity. Acta Neuropathol 131:309–319CrossRefGoogle Scholar
  11. Hirbe AC, Gutmann DH (2014) Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 13:834–843CrossRefGoogle Scholar
  12. Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, Niwa T, Takami H, Nakamura T, Suzuki T et al (2016) Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol 131:889–901CrossRefGoogle Scholar
  13. Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, Jones DT, Sturm D, Hermann C, Segura Wang M et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393CrossRefGoogle Scholar
  14. Jones DT, Hutter B, Jager N, Korshunov A, Kool M, Warnatz HJ, Zichner T, Lambert SR, Ryzhova M, Quang DA et al (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927–932CrossRefGoogle Scholar
  15. Jones C, Karajannis MA, Jones DT, Kieran MW, Monje M, Baker SJ, Becher OJ, Cho YJ, Gupta N, Hawkins C et al (2017) Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 19(2):153–161Google Scholar
  16. Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, Adoue V, Busche S, Caron M, Djambazian H et al (2014) Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat Genet 46:39–44CrossRefGoogle Scholar
  17. Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25:393–405CrossRefGoogle Scholar
  18. Korshunov A, Ryzhova M, Jones DT, Northcott PA, van Sluis P, Volckmann R, Koster J, Versteeg R, Cowdrey C, Perry A et al (2012) LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathol 124:875–881CrossRefGoogle Scholar
  19. Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678CrossRefGoogle Scholar
  20. Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, Ramaswamy V, Finlay J, Taylor MD, Dhall G et al (2016) Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatr Blood Cancer 63:1527CrossRefGoogle Scholar
  21. Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O (2014) BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniopharyngioma. Acta Neuropathol 127:927–929CrossRefGoogle Scholar
  22. Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857–861CrossRefGoogle Scholar
  23. Lin AL, Gutmann DH (2013) Advances in the treatment of neurofibromatosis-associated tumours. Nat Rev Clin Oncol 10:616–624CrossRefGoogle Scholar
  24. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820CrossRefGoogle Scholar
  25. Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, Wang X, Gallo M, Garzia L, Zayne K et al (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445–450CrossRefGoogle Scholar
  26. Mack SC, Agnihotri S, Bertrand KC, Wang X, Shih DJ, Witt H, Hill N, Zayne K, Barszczyk M, Ramaswamy V et al (2015) Spinal myxopapillary ependymomas demonstrate a Warburg phenotype. Clin Cancer Res 21:3750–3758CrossRefGoogle Scholar
  27. Merino DM, Shlien A, Villani A, Pienkowska M, Mack S, Ramaswamy V, Shih D, Tatevossian R, Novokmet A, Choufani S et al (2015) Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups. Clin Cancer Res 21:184–192CrossRefGoogle Scholar
  28. Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, Stavropoulos J, Alon N, Pole JD, Ray PN et al (2015) BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33:1015–1022CrossRefGoogle Scholar
  29. Nikbakht H, Panditharatna E, Mikael LG, Li R, Gayden T, Osmond M, Ho CY, Kambhampati M, Hwang EI, Faury D et al (2016) Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 7:11185CrossRefGoogle Scholar
  30. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD et al (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12:818–834CrossRefGoogle Scholar
  31. Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743CrossRefGoogle Scholar
  32. Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, Lee R, Tatevossian RG, Phoenix TN, Thiruvenkatam R et al (2014) C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature 506:451–455CrossRefGoogle Scholar
  33. Picard D, Miller S, Hawkins CE, Bouffet E, Rogers HA, Chan TS, Kim SK, Ra YS, Fangusaro J, Korshunov A et al (2012) Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 13:838–848CrossRefGoogle Scholar
  34. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JYH, Goumnerova LC, Black PM, Lau C et al (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436–442CrossRefGoogle Scholar
  35. Ramaswamy V, Northcott PA, Taylor MD (2011) FISH and chips: the recipe for improved prognostication and outcomes for children with medulloblastoma. Cancer Genet 204:577–588CrossRefGoogle Scholar
  36. Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho YJ, Shih DJ, Luu B, Dubuc AM, Northcott PA et al (2013) Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 14:1200–1207CrossRefGoogle Scholar
  37. Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones DT, Luu B, Cavalli FM, Aldape K et al (2016a) Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J Clin Oncol 34:2468CrossRefGoogle Scholar
  38. Ramaswamy V, Remke M, Adamski J, Bartels U, Tabori U, Wang X, Huang A, Hawkins C, Mabbott D, Laperriere N et al (2016b) Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients? Neuro-Oncology 18:291–297CrossRefGoogle Scholar
  39. Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford SC, Doz F, Kool M, Dufour C, Vassal G, Milde T et al (2016c) Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 131:821–831CrossRefGoogle Scholar
  40. Ramkissoon LA, Horowitz PM, Craig JM, Ramkissoon SH, Rich BE, Schumacher SE, McKenna A, Lawrence MS, Bergthold G, Brastianos PK et al (2013) Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110:8188–8193CrossRefGoogle Scholar
  41. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405CrossRefGoogle Scholar
  42. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231CrossRefGoogle Scholar
  43. Sekine S, Shibata T, Kokubu A, Morishita Y, Noguchi M, Nakanishi Y, Sakamoto M, Hirohashi S (2002) Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol 161:1997–2001CrossRefGoogle Scholar
  44. Shih DJ, Northcott PA, Remke M, Korshunov A, Ramaswamy V, Kool M, Luu B, Yao Y, Wang X, Dubuc AM et al (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886–896CrossRefGoogle Scholar
  45. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S et al (2015) Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 47:257–262CrossRefGoogle Scholar
  46. Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, Daly SB, Urquhart JE, Bholah Z, Oudit D et al (2014) Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 32:4155–4161CrossRefGoogle Scholar
  47. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437CrossRefGoogle Scholar
  48. Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072CrossRefGoogle Scholar
  49. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310CrossRefGoogle Scholar
  50. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472CrossRefGoogle Scholar
  51. Thomas C, Sill M, Ruland V, Witten A, Hartung S, Kordes U, Jeibmann A, Beschorner R, Keyvani K, Bergmann M et al (2016) Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups. Neuro-Oncology 18:790–796CrossRefGoogle Scholar
  52. Torchia J, Picard D, Lafay-Cousin L, Hawkins CE, Kim SK, Letourneau L, Ra YS, Ho KC, Chan TS, Sin-Chan P et al (2015) Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 16:569–582CrossRefGoogle Scholar
  53. Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D (2011) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12:559–567CrossRefGoogle Scholar
  54. Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, Nakamura H, He Z, Doddapaneni H, Lewis L et al (2014) Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511:241–245CrossRefGoogle Scholar
  55. Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I et al (2013) Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602–612CrossRefGoogle Scholar
  56. Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, Castelo-Branco P, Baskin B, Ray PN, Bouffet E et al (2013) Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 31:2927–2935CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Haematology/OncologyHospital for Sick ChildrenTorontoCanada
  2. 2.Developmental and Stem Cell BiologyHospital for Sick ChildrenTorontoCanada

Section editors and affiliations

  • James Thomas Rutka
    • 1
  1. 1.The Arthur and Sonia Labatt Brain Tumour Research CentreThe Hospital for Sick Children, The University of TorontoTorontoUSA

Personalised recommendations