Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 144 No. 4344 (2014)

Genetics and epigenetics of gliomas

  • Mario Luca Suvà
DOI
https://doi.org/10.4414/smw.2014.14018
Cite this as:
Swiss Med Wkly. 2014;144:w14018
Published
19.10.2014

Summary

Gliomas are the most common primary intrinsic brain tumours. Their classification is based on phenotypic resemblance to normal glial cells (astrocytomas, oligodendrogliomas, mixed oligoastrocytomas) and pathological grading. Whereas this system is clinically relevant and has been the basis for our understanding of gliomas, systematic use of next-generation sequencing has transformed our knowledge of their pathogenesis and has uncovered genetic changes in an unanticipated number of genes and regulatory elements. In the past few years, in-depth analysis of low-grade astrocytomas and glioblastomas in both paediatric and adult populations has clarified our molecular understanding of these diseases, with distinct molecular events occurring in different age groups. In oligodendrogliomas, recent studies have highlighted mutations in candidate tumour suppressor genes located on 1p/19q, chromosome arms frequently deleted in this tumour. In this review, we discuss recent discoveries in the genetics of adult and paediatric gliomas, and highlight how some of the founding genetic mutations reshape the cancer epigenome. These studies provide an in-depth view of the molecular routes leading to brain tumour development and will be key for refining classification systems and improving clinical care.

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10) p.987–96.
  2. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al., Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):p.709–22.
  3. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):p.699–708.
  4. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al., Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):p.2507–16.
  5. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):p.2129–39.
  6. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):p.783–92.
  7. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):p.1031–7.
  8. Kwak EL, BangYJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010. 363(18): p. 1693–703.
  9. Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26(8):p.756–84.
  10. 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):p.810–7.
  11. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma, in Science. United States. 2014;p.1396–401.
  12. Parker BC, Annala MJ, Cogdell DE, Granberg KJ, Sun Y, Ji P, et al. The tumorigenic FGFR3–TACC3 gene fusion escapes miR-99a regulation in glioblastoma. J Clin Invest. 2013;123(2):p.855–65.
  13. Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012;337(6099):p.1231–5.
  14. Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet. 2013;45(10):p.1141–9.
  15. Schonberg DL, Bao S, Rich JN. Genomics informs glioblastoma biology. Nat Genet. 2013;45(10):p.1105–7.
  16. Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan S, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet, 2013. 45(3): p. 253–61.
  17. Rheinbay E, Suva ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, et al. An Aberrant Transcription Factor Network Essential for Wnt Signaling and Stem Cell Maintenance in Glioblastoma. Cell Rep. 2013;3(5):p.1567–79.
  18. Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014;157(3):p.580–94.
  19. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):p.1807–12.
  20. Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Cosper AK, Dias-Santagata D, et al. A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J Neuropathol Exp Neurol. 2011;70(2):p.110–5.
  21. Juratli TA, Kirsch M, Robel K, Soucek S, Geiger K, von Kummer R, et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol. 2012;108(3):p.403–10.
  22. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012;3(7):p.709–22.
  23. Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, et al. Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget. 2012;3(10):p.1194–203.
  24. Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124(5):p.615–25.
  25. Abedalthagafi M, Phillips JJ, Kim GE, Mueller S, Haas-Kogen DA, Marshall RE, et al. The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas. Mod Pathol. 2013.
  26. Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D, Korshunov A, et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 2013;125(5):p.659–69.
  27. Chi AS, Batchelor TT, Yang D, Dias-Santagata D, Borger DR, Ellisen LW, et al. BRAF V600E mutation identifies a subset of low-grade diffusely infiltrating gliomas in adults. J Clin Oncol. 2013;31(14):p.e233–6.
  28. Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma, in Science. 2011;United States:p.1453–5.
  29. 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):p.7–16.
  30. Badiali M, Gleize V, Paris S, Moi L, Elhouadani S, Arcella A, et al. KIAA1549–BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults. Brain Pathol. 2012;22(6):p.841–7.
  31. Kim YH, Nonoguchi N, Paulus W, Brokinkel B, Keyvani K, Sure U, et al. Frequent BRAF gain in low-grade diffuse gliomas with 1p/19q loss. Brain Pathol. 2012;22(6):p.834–40.
  32. Zhang PJ, Wu G, Miller CP, Tatevossian RG, Dalton JD, et al. St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome, Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45(6):p.602–12.
  33. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):p.226–31.
  34. 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.
  35. 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):p.425–37.
  36. Aihara K, Mukasa A, Gotoh K, Saito K, Nagae G, Tsuji S, et al. H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro Oncol. 2014;16(1):p.140–6.
  37. Yuen BT, Knoepfler PS. Histone H3.3 mutations: a variant path to cancer. Cancer Cell. 2013;24(5):p.567–74.
  38. Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA. 2012;307(10):p.1062–71.
  39. Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340(6134):p.857–61.
  40. Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, et al. Evaluation of Histone 3 Lysine 27 Trimethylation (H3K27me3) and Enhancer of Zest 2 (EZH2) in Pediatric Glial and Glioneuronal Tumors Shows Decreased H3K27me3 in H3F3A K27M Mutant Glioblastomas. Brain Pathol. 2013.
  41. Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009;69(24):p.9211–8.
  42. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13(1):p.69–80.
  43. Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, et al. Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN. Cancer Discov. 2013.
  44. Losman JA, Kaelin WG, Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2–hydroxyglutarate, and cancer. Genes Dev. 2013;27(8):p.836–52.
  45. 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):p.765–73.
  46. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):p.479–83.
  47. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2–hydroxyglutarate. Nature. 2009;462(7274):p.739–44.
  48. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):p.553–67.
  49. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5–methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):p.839–43.
  50. Kim YH, Pierscianek D, Mittelbronn M, Vital A, Mariani L, Hasselblatt M, et al. TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J Clin Pathol. 2011;64(10):p.850–2.
  51. Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, et al. MGMT testing-the challenges for biomarker-based glioma treatment, in Nat Rev Neurol. 2014: England. p. 372–85.
  52. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial, in Lancet Oncol. England. 2012;p.707–15.
  53. Comprehensive genomic characterization defines human glioblastoma genes and core pathways, in Nature. England. 2008;p.1061–8.
  54. Suva M., Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339(6127):p.1567–70.
  55. Louis, D.N., The next step in brain tumor classification: "Let us now praise famous men"… or molecules? Acta Neuropathol. 2012;124(6):p.761–2.