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Genomic Applications in Brain Tumors

  • Matija SnuderlEmail author
Chapter

Abstract

For almost 100 years, brain tumors have been defined by their histopathological features. However, advances in molecular biology research have expanded our ability to diagnose and classify brain tumors and provide necessary information for clinical management. Understanding of mutations and pathways involved in the development of brain tumors helps to distinguish clinically distinct subgroups and adjust therapy to reflect the biology of the disease. Furthermore, discovery of driving mechanisms and pathways will help provide potential therapeutic targets. The most recent reiteration of WHO classification has largely adopted molecular approach for diagnosis and classification of brain tumors. Several molecular tests have been used in clinical practice. While some current molecular assays are focused on one target or a few targets, there is increasing role of large gene panel, whole-exome, and whole-genome analysis. We discuss the practical utility of molecular tests for diagnosis and clinical management of patients with brain tumors, as well as the recent discoveries in brain tumor genetics and epigenetics.

Keywords

Neuro-oncology Neuropathology IDH1/2 1p/19q MGMT ATRX EGFR BRAF Shh glioma Glioblastoma Oligodendroglioma Medulloblastoma Ependymoma RELA 

References

  1. 1.
    Riemenschneider MJ, Jeuken JW, Wesseling P, Reifenberger G. Molecular diagnostics of gliomas: state of the art. Acta Neuropathol. 2010;120(5):567–84.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Tabatabai G, Stupp R, van den Bent MJ, Hegi ME, Tonn JC, Wick W, et al. Molecular diagnostics of gliomas: the clinical perspective. Acta Neuropathol. 2010;120(5):585–92.PubMedGoogle Scholar
  3. 3.
    von Deimling A, Korshunov A, Hartmann C. The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations. Brain Pathol. 2011;21(1):74–87.Google Scholar
  4. 4.
    Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333(6048):1453–5.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012;226(1):7–16.PubMedGoogle Scholar
  6. 6.
    Horbinski C, Miller CR, Perry A. Gone FISHing: clinical lessons learned in brain tumor molecular diagnostics over the last decade. Brain Pathol. 2011;21(1):57–73.PubMedGoogle Scholar
  7. 7.
    Snuderl M, Eichler AF, Ligon KL, Vu QU, Silver M, Betensky RA, et al. Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss. Clin Cancer Res. 2009;15(20):6430–7.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Wiens AL, Cheng L, Bertsch EC, Johnson KA, Zhang S, Hattab EM. Polysomy of chromosomes 1 and/or 19 is common and associated with less favorable clinical outcome in oligodendrogliomas: fluorescent in situ hybridization analysis of 84 consecutive cases. J Neuropathol Exp Neurol. 2012;71(7):618–24.PubMedGoogle Scholar
  9. 9.
    Sahm F, Reuss D, Koelsche C, Capper D, Schittenhelm J, Heim S, et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 2014;128(4):551–9.PubMedGoogle Scholar
  10. 10.
    Unruh D, Schwarze SR, Khoury L, Thomas C, Wu M, Chen L, et al. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol. 2016;132(6):917–30.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Chen H, Judkins J, Thomas C, Wu M, Khoury L, Benjamin CG, et al. Mutant IDH1 and seizures in patients with glioma. Neurology. 2017;88(19):1805–13.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Huse JT, Diamond EL, Wang L, Rosenblum MK. Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”? Acta Neuropathol. 2015;129(1):151–3.PubMedGoogle Scholar
  13. 13.
    Olar A, Wani KM, Alfaro-Munoz KD, Heathcock LE, van Thuijl HF, Gilbert MR, et al. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Acta Neuropathol. 2015;129(4):585–96.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–93.PubMedGoogle Scholar
  15. 15.
    Richardson TE, Snuderl M, Serrano J, Karajannis MA, Heguy A, Oliver D, et al. Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis. J Neuro-Oncol. 2017;133(1):183–92.Google Scholar
  16. 16.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319–25.PubMedGoogle Scholar
  18. 18.
    Joensuu H, Puputti M, Sihto H, Tynninen O, Nupponen NN. Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol. 2005;207(2):224–31.PubMedGoogle Scholar
  19. 19.
    Puputti M, Tynninen O, Sihto H, Blom T, Maenpaa H, Isola J, et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res. 2006;4(12):927–34.PubMedGoogle Scholar
  20. 20.
    Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, et al. Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer. 1994;56(1):72–7.PubMedGoogle Scholar
  21. 21.
    Pierscianek D, Kim YH, Motomura K, Mittelbronn M, Paulus W, Brokinkel B, et al. MET gain in diffuse astrocytomas is associated with poorer outcome. Brain Pathol. 2013;23(1):13–8.PubMedGoogle Scholar
  22. 22.
    Hobbs J, Nikiforova MN, Fardo DW, Bortoluzzi S, Cieply K, Hamilton RL, et al. Paradoxical relationship between the degree of EGFR amplification and outcome in glioblastomas. Am J Surg Pathol. 2012;36(8):1186–93.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Horbinski C. To BRAF or not to BRAF: is that even a question anymore? J Neuropathol Exp Neurol. 2013;72(1):2–7.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol. 2017;35(25):2934–41.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, et al. CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res. 2004;10(15):4933–8.PubMedGoogle Scholar
  26. 26.
    Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004;10(6):1871–4.PubMedGoogle Scholar
  27. 27.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.PubMedGoogle Scholar
  28. 28.
    Cankovic M, Nikiforova MN, Snuderl M, Adesina AM, Lindeman N, Wen PY, et al. The role of MGMT testing in clinical practice: a report of the association for molecular pathology. J Mol Diagn. 2013;15(5):539–55.PubMedGoogle Scholar
  29. 29.
    Eberhart CG. Molecular diagnostics in embryonal brain tumors. Brain Pathol. 2011;21(1):96–104.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27(5):728–43.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Orillac C, Thomas C, Dastagirzada Y, Hidalgo ET, Golfinos JG, Zagzag D, et al. Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation. Acta Neuropathol Commun. 2016;4(1):84.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Gajjar A, Bowers DC, Karajannis MA, Leary S, Witt H, Gottardo NG. Pediatric brain tumors: innovative genomic information is transforming the diagnostic and clinical landscape. J Clin Oncol. 2015;33(27):2986–98.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488(7409):106–10.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12(12):818–34.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–14.PubMedGoogle Scholar
  36. 36.
    Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488(7409):49–56.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129(5):669–78.PubMedGoogle Scholar
  38. 38.
    Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72.PubMedGoogle Scholar
  39. 39.
    Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, 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. 2012;123(4):473–84.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326(5952):572–4.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488(7409):100–5.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–26.PubMedGoogle Scholar
  44. 44.
    Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22(4):425–37.PubMedGoogle Scholar
  46. 46.
    Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013;125(6):913–6.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45(6):602–12.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Paugh BS, Zhu X, Qu C, Endersby R, Diaz AK, Zhang J, et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res. 2013;73(20):6219–29.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124(3):439–47.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–3.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Huse JT, Snuderl M, Jones DTW, Brathwaite CD, Altman N, Lavi E, et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol. 2017;133(3):417–29.PubMedGoogle Scholar
  53. 53.
    Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A. 2012;109(8):3041–6.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20(6):810–7.PubMedGoogle Scholar
  55. 55.
    Little SE, Popov S, Jury A, Bax DA, Doey L, Al-Sarraj S, et al. Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. Cancer Res. 2012;72(7):1614–20.PubMedGoogle Scholar
  56. 56.
    Motomura K, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U, et al. PDGFRA gain in low-grade diffuse gliomas. J Neuropathol Exp Neurol. 2013;72(1):61–6.PubMedGoogle Scholar
  57. 57.
    Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.PubMedGoogle Scholar
  58. 58.
    Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339(6123):1077–80.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Reuss DE, Piro RM, Jones DT, Simon M, Ketter R, Kool M, et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol. 2013;125(3):351–8.PubMedGoogle Scholar
  60. 60.
    Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017;18(5):682–94.PubMedGoogle Scholar
  61. 61.
    Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol. 2010;28(19):3182–90.PubMedGoogle Scholar
  62. 62.
    Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014;506(7489):445–50.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 2011;20(2):143–57.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell. 2016;164(5):1060–72.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016;29(3):379–93.PubMedGoogle Scholar
  66. 66.
    Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol. 2011;29(11):1424–30.PubMedGoogle Scholar
  67. 67.
    Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31(6):737–54. e6.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PathologyNYU Langone Medical Center and Medical SchoolNew YorkUSA

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