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Molecular Pathology and Diagnostics of Gliomas

  • Jesse Kresak
  • Yuan (Frank) ShanEmail author
Chapter
Part of the Cancer Growth and Progression book series (CAGP, volume 16)

Abstract

Gliomas are the most common primary malignancy in the central nervous system. With recent advancements in molecular pathology, pathologists now have additional tools for histologic analysis of these brain tumors. Genomic and proteomic studies may aid in the diagnosis of gliomas, as well as have utility in prognostication and response to treatment options. Presented are the most current molecular studies utilized in neuropathology of gliomas, as well as a glimpse to future potential biomarkers.

Keywords

Gliomas Genomics Proteomics IDH1 p53 1p/19q EGFR 

Abbreviations

2HG

(R)-2-hydroxyglutarate

COBRA

Combined bisulfite restriction analysis

EGFR

Epidermal growth factor receptor

FISH

Fluorescent in situ hybridization

IDH

Isocitrate dehydrogenase

LOH

Loss of heterozygosity

MALDI-TOF

Matrix assisted laser desorption ionization—time of flight

MAPK

Mitogen-activated protein kinase

MGMT

O6-methylguanine-DNA methyltransferase

miRNA

microRNA

MMP

Matrix metalloproteinase

MS

Mass spectroscopy

MS-MLPA

Methylation-specific multiplex ligation-dependent probe amplification

PTEN

Phosphatase and tensin homolog

RT-PCR

Reverse transcription-polymerase chain reaction

SELDI-TOF

Surface enhanced laser desorption ionization—time of flight

WHO

World Health Organization

References

  1. 1.
    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 114:97–109PubMedCrossRefGoogle Scholar
  2. 2.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedCrossRefGoogle Scholar
  3. 3.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedCrossRefGoogle Scholar
  4. 4.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744PubMedCrossRefGoogle Scholar
  5. 5.
    Aghili M, Zahedi F, Rafiee E (2009) Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91:233–236PubMedCrossRefGoogle Scholar
  6. 6.
    Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265PubMedCrossRefGoogle Scholar
  7. 7.
    Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, Dang L, Fantin VR, Mak TW (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344PubMedCrossRefGoogle Scholar
  8. 8.
    Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154PubMedCrossRefGoogle Scholar
  9. 9.
    Gravendeel LA, Kloosterhof NK, Bralten LB, van Marion R, Dubbink HJ, Dinjens W, Bleeker FE, Hoogenraad CC, Michiels E, Kros JM, van den Bent M, Smitt PA, French PJ (2010) Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma. Hum Mutat 31:E1186–E1199PubMedCrossRefGoogle Scholar
  10. 10.
    van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, Frenay M, Tijssen CC, Lacombe D, Idbaih A, van Marion R, Kros JM, Dinjens WN, Gorlia T, Sanson M (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16:1597–1604PubMedCrossRefGoogle Scholar
  11. 11.
    Kato Y, Jin G, Kuan CT, McLendon RE, Yan H, Bigner DD (2009) A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma derived mutation. Biochem Biophys Res Commun 390:547–551PubMedCrossRefGoogle Scholar
  12. 12.
    Capper D, Weissert S, Balss J, Habel A, Meyer J, Jäger D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H, Hartmann C, von Deimling A (2009) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254PubMedCrossRefGoogle Scholar
  13. 13.
    Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol 118:599–601PubMedCrossRefGoogle Scholar
  14. 14.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354PubMedCrossRefGoogle Scholar
  15. 15.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  16. 16.
    Reimenschneider M, Jeuken JW, Wesseling P, Reifenberger G (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120:567–584CrossRefGoogle Scholar
  17. 17.
    Pollack IF, Hamilton RL, Sobol RW, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 cohort. J Clin Oncol 24:3431–3437PubMedCrossRefGoogle Scholar
  18. 18.
    Schlosser S, Wagner S, Muhlisch J, Hasselblatt M, Gerss J, Wolff JE, Frühwald MC (2010) MGMT as a potential stratification marker in relapsed high-grade glioma of children: the HIT-GBM experience. Pediatr Blood Cancer 54:228–237PubMedGoogle Scholar
  19. 19.
    Nikiforova M, Hamilton R (2011) Molecular diagnostics of gliomas. Arch Pathol Lab Med 135:558–568PubMedGoogle Scholar
  20. 20.
    Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121PubMedCrossRefGoogle Scholar
  21. 21.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  22. 22.
    Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880PubMedCrossRefGoogle Scholar
  23. 23.
    Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME (2010) MGMT promotor methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedCrossRefGoogle Scholar
  24. 24.
    Mikeska T, Bock C, El-Maarri O, Hübner A, Ehrentraut D, Schramm J, Felsberg J, Kahl P, Büttner R, Pietsch T, Waha A (2007) Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J Mol Diagn 9:368–381PubMedCrossRefGoogle Scholar
  25. 25.
    Levidou G, El-Habr E, Saetta AA, Bamias C, Katsouyanni K, Patsouris E, Korkolopoulou P (2010) P53 immunoexpression as a prognostic marker for human astrocytomas: a meta-analysis and review of the literature. J Neurooncol 100:363–371PubMedCrossRefGoogle Scholar
  26. 26.
    Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489PubMedGoogle Scholar
  27. 27.
    Nieder C, Petersen S, Petersen C, Thames HD (2000) The challenge of p53 as prognostic and predictive factor in gliomas. Cancer Treat Rev 26:67–73PubMedCrossRefGoogle Scholar
  28. 28.
    Jeuken JW, von Deimling A, Wesseling P (2004) Molecular pathogenesis of oligodendroglial tumors. J Neurooncol 70:161–181PubMedCrossRefGoogle Scholar
  29. 29.
    Cairncross G, Jenkins R (2008) Gliomas with 1p/19q codeletion: a.k.a. oligodendroglioma. Cancer J 14:352–357PubMedCrossRefGoogle Scholar
  30. 30.
    Scheie D, Cvancarova M, Mork S, Skullerud K, Andresen PA, Benestad I, Helseth E, Meling T, Beiske K (2008) Can morphology predict 1p/19q loss in oligodendroglial tumours? Histopathology 53:578–587PubMedCrossRefGoogle Scholar
  31. 31.
    Idbaih A, Marie Y, Pierron G, Brennetot C, Hoang-Xuan K, Kujas M, Mokhtari K, Sanson M, Lejeune J, Aurias A, Delattre O, Delattre JY (2005) Two types of chromosome 1p losses with opposite significance in gliomas. Ann Neurol 58:483–487PubMedCrossRefGoogle Scholar
  32. 32.
    Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549: BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119–2123PubMedCrossRefGoogle Scholar
  33. 33.
    Korshunov A, Meyer J, Capper D, Christians A, Remke M, Witt H, Pfister S, von Deimling A, Hartmann C (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118:401–405PubMedCrossRefGoogle Scholar
  34. 34.
    Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P (2008) BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739–1749PubMedCrossRefGoogle Scholar
  35. 35.
    Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13:2038–2045PubMedCrossRefGoogle Scholar
  36. 36.
    Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15:4622–4629PubMedCrossRefGoogle Scholar
  37. 37.
    Deighton RF, McGregor R, Kemp J, McColloch J, Whittle I (2010) Glioma pathophysiology: insights emerging from proteomics. Brain Pathol 20:691–703PubMedCrossRefGoogle Scholar
  38. 38.
    Chumbalkar V, Subhashini C, Dhople VM, Sundaram CS, Jagannadham MV, Kumar KN, Srinivas PN, Mythili R, Rao MK, Kulkarni MJ, Hegde S, Hegde AS, Samual C, Santosh V, Singh L, Sirdeshmukh R (2005) Differential protein expression in human gliomas and molecular insights. Proteomics 5:1167–1177PubMedCrossRefGoogle Scholar
  39. 39.
    Nagane M, Coufal F, Lin H, Bögler O, Cavenee WK, Huang HJ (1996) A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res 56:5079–5086PubMedGoogle Scholar
  40. 40.
    Gan HK, Kaye AH, Luwor RB (2009) The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 16:748–754PubMedCrossRefGoogle Scholar
  41. 41.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  42. 42.
    Kapoor GS, O'Rourke DM (2003) Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther 2:330–342PubMedGoogle Scholar
  43. 43.
    Ohgaki H, Kleihues P (2009) Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:2235–2241PubMedCrossRefGoogle Scholar
  44. 44.
    Mishra S, Murphy LC, Murphy LJ (2006) The Prohibitins: emerging roles in diverse functions. J Cell Mol Med 10:353–363PubMedCrossRefGoogle Scholar
  45. 45.
    Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) DH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153PubMedCrossRefGoogle Scholar
  46. 46.
    Labussiere M, Idbaih A, Wang XW, Marie Y, Boisselier B, Falet C, Paris S, Laffaire J, Carpentier C, Crinière E, Ducray F, El Hallani S, Mokhtari K, Hoang-Xuan K, Delattre JY, Sanson M (2010) All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 74:1886–1890PubMedCrossRefGoogle Scholar
  47. 47.
    Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061–3068PubMedCrossRefGoogle Scholar
  48. 48.
    Novakova J, Slaby O, Vyzula R, Michalek J (2009) MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun 386:1–5PubMedCrossRefGoogle Scholar
  49. 49.
    Cho WC (2007) OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 6:60PubMedCrossRefGoogle Scholar
  50. 50.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334:1351–1358PubMedCrossRefGoogle Scholar
  51. 51.
    Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65:6029–6033PubMedCrossRefGoogle Scholar
  52. 52.
    Silber J, James CD, Hodgson JG (2009) MicroRNAs in gliomas: small regulators of a big problem. Neuromolecular Med 11:208–222PubMedCrossRefGoogle Scholar
  53. 53.
    Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, Cai X, Wang K, Wang G, Ba Y, Zhu L, Wang J, Yang R, Zhang Y, Ren Z, Zen K, Zhang J, Zhang CY (2009) Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 28:1385–1392PubMedCrossRefGoogle Scholar
  54. 54.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57PubMedCrossRefGoogle Scholar
  55. 55.
    daFonseca CO, Linden R, Futuro D, Gattass CR, Quiric-Santos T (2008) Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol. Arch Immunol Ther Exp 56:267–276CrossRefGoogle Scholar
  56. 56.
    Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68:8164–8172PubMedCrossRefGoogle Scholar
  57. 57.
    Nakada M, Okada Y, Yamashita J (2003) The role of matrix metalloproteinases in glioma invasion. Front Biosci 8:e261–e269PubMedCrossRefGoogle Scholar
  58. 58.
    le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, Anile C, Maira G, Mercatelli N, Ciafrè SA, Farace MG, Agami R (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26:3699–3708PubMedCrossRefGoogle Scholar
  59. 59.
    Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, You Y (2008) hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res 1236:185–193PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X, Gong Y, Yin B, Liu W, Qiang B, Zhao J, Yuan J, Peng X (2009) MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med 87:43–51PubMedCrossRefGoogle Scholar
  61. 61.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S (2008) Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68:9125–9130PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.University of South FloridaTampaUSA
  2. 2.Department of Anatomic PathologyMoffitt Cancer Center & Research InstituteTampaUSA

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