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Pathology & Oncology Research
Published in: Pathology & Oncology Research 1/2019

01-01-2019 | Original Article

Molecular Subgroups of Glioblastoma– an Assessment by Immunohistochemical Markers

Authors: Ádám Nagy, Ferenc Garzuly, Gergely Padányi, Iván Szűcs, Ádám Feldmann, Balázs Murnyák, Tibor Hortobágyi, Bernadette Kálmán

Published in: Pathology & Oncology Research | Issue 1/2019

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Abstract

Comprehensive molecular characterization of and novel therapeutic approaches to glioblastoma have been explored as a result of advancements in biotechnologies. In this study, we aimed to bring basic research discoveries closer to clinical practice and ultimately incorporate molecular classification into the routine histopathological evaluation of grade IV gliomas. Integrated results of genome-wide sequencing, transcriptomic and epigenomic analyses by The Cancer Genome Atlas Network defined the classic, proneural, neural and mesenchymal subtypes of this tumor. In a retrospective cohort, we analyzed selected subgroup-defining molecular markers in formalin-fixed paraffin-embedded surgical specimens by immunohistochemistry. Quantitative and qualitative scores of marker expression were tested in hierarchical cluster analyses to evaluate segregations of the molecular subgroups, which then were correlated with clinical parameters including patients’ age, gender and overall survival. Our study has confirmed the separation of molecular glioblastoma subgroups with clear trends regarding clinical correlations. Future analyses in a larger, prospective cohort using similar methods are expected to facilitate the development of a molecular diagnostic panel that may complement routine histological work up and support prognostication as well as treatment decisions in glioblastoma.
Literature
1.
Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996CrossRefPubMed
2.
Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH et al (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303(23):1323–1329CrossRefPubMed
3.
Laperriere N, Zuraw L, Cairncross G, Cancer Care Ontario Practice Guidelines Initiative Neuro-Oncology Disease Site Group (2002) Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 64(3):259–273CrossRefPubMed
4.
Chaurasia A, Park SH, Seo JW, Park CK (2016) Immunohistochemical analysis of ATRX, IDH1 and p53 in Glioblastoma and their correlations with patient survival. J Korean Med Sci 31(8):1208–1214CrossRefPubMedPubMedCentral
5.
Eidel O, Burth S, Neumann JO, Kieslich PJ, Sahm F, Jungk C et al (2017) Tumor infiltration in enhancing and non-enhancing parts of Glioblastoma: a correlation with histopathology. PLoS One 12(1):e0169292CrossRefPubMedPubMedCentral
6.
The Cancer Genome Atlas (TCGA) Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRef
7.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110CrossRefPubMedPubMedCentral
8.
9.
Aubry M, de Tayrac M, Etcheverry A, Clavreul A, Saikali S, Menei P et al (2016) From the core to beyond the margin: a genomic picture of glioblastoma intratumor heterogeneity. Oncotarget 6(14):12094–12109
10.
Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522CrossRefPubMedPubMedCentral
11.
Segerman A, Niklasson M, Haglund C, Bergström T, Jarvius M, Xie Y et al (2016) Clonal variation in drug and radiation response among Glioma-initiating cells is linked to proneural-Mesenchymal transition. Cell Rep 17(11):2994–3009CrossRefPubMed
12.
He ZC, Ping YF, Xu SL, Lin Y, Yu SC, Kung HF et al (2015) Lower MGMT expression predicts better prognosis in proneural-like glioblastoma. Int J Clin Exp Med 8(11):20287–20294PubMedPubMedCentral
13.
Myung JK, jin Cho H, Kim H, Park CK, Lee SH, Choi SH et al (2014) Prognosis of glioblastoma with oligodendroglioma component is associated with the IDH1 mutation and MGMT methylation status. Transl Oncol 7(6):712–719CrossRefPubMedPubMedCentral
14.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WKet al. (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820CrossRefPubMed
15.
Le Mercier M, Hastir D, Lopez XM, De Neve N, Maris C, Trepant AL et al (2012) A simplified approach for the molecular classification of glioblastomas. PLoS One 7(9):e45475CrossRefPubMedPubMedCentral
16.
Lee KS, Choe G, Nam KH, Seo AN, Yun S, Kim KJ et al (2013) Immunohistochemical classification of primary and secondary glioblastomas. Korean J Pathol 47(6):541–548CrossRefPubMedPubMedCentral
17.
Conroy S, Kruyt FA, Joseph JV, Balasubramaniyan V, Bhat KP, Wagemakers M et al (2014) Subclassification of newly diagnosed glioblastomas through an immunohistochemical approach. PLoS One 9(12):e115687CrossRefPubMedPubMedCentral
18.
Esteve-Codina A, Arpi O, Martinez-García M, Pineda E, Mallo M, Gut M et al (2017) A comparison of RNA-Seq results from paired formalin-fixed paraffin-embedded and fresh-frozen Glioblastoma tissue samples. PLoS One 12(1):e0170632CrossRefPubMedPubMedCentral
19.
Colman H, Zhang Z, Sulma EP, McDonald JM, Shooshtari NL, Rivera A et al (2010) A multigene predictor of outcome in glioblastoma. Neuro-Oncology 12(1):49–57CrossRefPubMed
20.
Joseph NM, Phillips J, Dahiya S, Felicella MM, Tihan T, Brat DJ et al (2013) Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. Mod Pathol 26(3):315–326CrossRefPubMed
21.
Chen L, Lin ZX, Li GS, Zhou CF, Chen YP, Wang XF et al (2015) Classification of microvascular patterns via cluster analysis reveals their prognostic significance in glioblastoma. Hum Pathol 46(1):120–128CrossRefPubMed
22.
Denicolaï E, Tabouret E, Colin C, Metellus P, Nanni I, Boucard C et al (2016) Molecular heterogeneity of glioblastomas: does location matter? Oncotarget 7(1):902–913CrossRefPubMed
23.
Cai J, Zhang C, Zhan W, Wang G, Yao K, Wang Z et al (2016) ATRX, IDH1-R132H and Ki-67 immunohistochemistry as a classification scheme for astrocytic tumors. Oncoscience 3(7–8):258–265PubMedPubMedCentral
24.
Kalman B, Szep E, Garzuly F (2013) Post DE. Epidermal growth factor receptor as a therapeutic target in glioblastoma. NeuroMolecular Med 15(2):420–434CrossRefPubMed
25.
Lindberg OR, McKinney A, Engler JR, Koshkakaryan G, Gong H, Robinson AE et al (2016) GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity. Oncotarget 7(48):79101–79116CrossRefPubMedPubMedCentral
26.
Vizcaíno MA, Shah S, Eberhart CG, Rodriguez FJ (2015) Clinicopathologic implications of NF1 gene alterations in diffuse gliomas. Hum Pathol 46(9):1323–1330CrossRefPubMedPubMedCentral
27.
Xie B, Fan X, Lei Y, Chen R, Wang J, Fu C et al (2016) A novel de novo microdeletion at 17q11. 2 adjacent to NF1 gene associated with developmental delay, short stature, microcephaly and dysmorphic features. Mol Cytogenet 9(1):31–41CrossRef
28.
Way GP, Allaway RJ, Bouley SJ, Fadul CE, Sanchez Y, Greene CS (2017) A machine learning classifier trained on cancer transcriptomes detects NF1 inactivation signal in glioblastoma. BMC Genomics 18(1):127–128CrossRefPubMedPubMedCentral
29.
Nagy A, Eder K, Selak MA, Kalman B (2015) Mitochondrial energy metabolism and apoptosis regulation in glioblastoma. Brain Res 1595:127–142CrossRefPubMed
30.
Setty P, Hammes J, Rothämel T, Vladimirova V, Kramm CM, Pietsch T et al (2010) A pyrosequencing-based assay for the rapid detection of IDH1 mutations in clinical samples. J Mol Diagn 12(6):750–756CrossRefPubMedPubMedCentral
31.
Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M et al (2016) Expression of Idh1 R132H in the murine subventricular zone stem cell niche recapitulates features of early Gliomagenesis. Cancer Cell 30(4):578–594CrossRefPubMedPubMedCentral
32.
Zhu H, Zhang Y, Chen J, Qiu J, Huang K, Wu M, Xia C (2017) IDH1 R132H mutation enhances cell migration by activating AKT-mTOR signaling pathway, but sensitizes cells to 5-FU treatment as NADPH and GSH are reduced. PLoS One 12(1):e0169038CrossRefPubMedPubMedCentral
33.
Yoon KS, Lee MC, Kang SS, Kim JH, Jung S, Kim YJ et al (2001) p53 mutation and epidermal growth factor receptor overexpression in glioblastoma. J Korean Med Sci 16(4):481–488CrossRefPubMedPubMedCentral
34.
Liu Y, Wang F, Liu Y, Yao Y, Lv X, Dong B et al (2016) RNF135, RING finger protein, promotes the proliferation of human glioblastoma cells in vivo and in vitro via the ERK pathway. Sci Rep 6:e20624CrossRef
35.
Stieber D, Golebiewska A, Evers L, Lenkiewicz E, Brons NH, Nicot N et al (2014) Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes. Acta Neuropathol 127(2):203–219CrossRefPubMed
36.
Cancer Genome Atlas (TCGA) Research Network (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517(7536):576–582CrossRef
37.
Eckel-Passow JE, Lachanc DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372(26):2499–2508CrossRefPubMedPubMedCentral
38.
39.
Murnyák B, Csonka T, Klekner Á, Hortobágyi T (2013) Occurrence and molecular pathology of low grade gliomas. Alacsony grádusú gliális daganatok előfordulása és molekuláris patológiája. (in Hungarian) Ideggyógyászati Szemle/Clinical. Neuroscience 66:305–311
40.
Murnyák B, Csonka T, Hegyi K, Méhes G, Klekner Á, Hortobágyi T (2013) Occurrence and molecular pathology of high grade gliomas. (Magas grádusú gliomák előfordulása és molekuláris patológiája.) (in Hungarian) Ideggyógyászati Szemle/Clinical. Neuroscience 66:312–321
41.
McKeever PE, Dennis TR, Burgess AC, Meltzer PS, Marchuk DA, Trent JM (1996) Chromosome breakpoint at 17q11. 2 and insertion of DNA from three different chromosomes in a glioblastoma with exceptional glial fibrillary acidic protein expression. Cancer Genet Cytogenet 87(1):41–47CrossRefPubMed
42.
Vandenbroucke I, Van Oostveldt P, Coene E, De Paepe A, Messiaen L (2004) Neurofibromin is actively transported to the nucleus. FEBS Lett 560(1–3):98–102CrossRefPubMed
43.
Liu YC, Wang YZ (2015) Role of yes-associated protein 1 in gliomas: pathologic and therapeutic aspects. Tumor Biol 36(4):2223–2227CrossRef
44.
Kondo I, Shimizu N (1983) Mapping of the human gene for epidermal growth factor receptor (EGFR) on the p13→ q22 region of chromosome 7. Cytogenet Genome Res 35(1):9–14CrossRef
45.
Lopez-Gines C, Gil-Benso R, Ferrer-Luna R, Benito R, Serna E, Gonzalez-Darder J et al (2010) New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile. Mod Pathol 23(6):856–865CrossRefPubMed
46.
Dasari VR, Velpula KK, Alapati K, Gujrati M, Tsung AJ (2012) Cord blood stem cells inhibit epidermal growth factor receptor translocation to mitochondria in glioblastoma. PLoS One 7(2):e31884CrossRefPubMedPubMedCentral
47.
Csonka T, Murnyák B, Szepesi R, Kurucz A, Klekner Á, Hortobágyi T (2014) Poly(ADP-ribose) polymerase-1 (PARP1) and p53 labelling index correlates with tumour grade in meningiomas. Folia Neuropathol 52:111–120CrossRefPubMed
48.
Csonka T, Murnyák B, Szepesi R, Bencze J, Bognár L, Klekner Á, Hortobágyi T (2016) Assessment of candidate immunohistochemical prognostic markers of meningioma recurrence. Folia Neuropathol 54:114–126CrossRefPubMed
49.
50.
51.
Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ (1987) Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci 84(21):7716–7719CrossRefPubMedPubMedCentral
52.
England B, Huang T, Karsy M (2013) Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumor Biol 34(4):2063–2074CrossRef
53.
Smardova J, Liskova K, Ravcukova B, Kubiczkova L, Sevcikova S, Michalek J et al (2013) High frequency of temperature-sensitive mutants of p53 in Glioblastoma. Pathol Oncol Res 19(3):421–428CrossRefPubMed
54.
Kawasoe T, Takeshima H, Yamashit S, Mizuguch S, Fukushima T, Yokogami K et al (2015) Detection of p53 mutations in proliferating vascular cells in glioblastoma multiforme. J Neurosurg 122(2):317–323CrossRefPubMed
Metadata
Title
Molecular Subgroups of Glioblastoma– an Assessment by Immunohistochemical Markers
Authors
Ádám Nagy
Ferenc Garzuly
Gergely Padányi
Iván Szűcs
Ádám Feldmann
Balázs Murnyák
Tibor Hortobágyi
Bernadette Kálmán
Publication date
01-01-2019
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 1/2019
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-017-0311-6

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