A Glioblastoma Genomics Primer for Clinicians

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John D Patterson, BS Thidathip Wongsurawat, PhD Analiz Rodriguez, MD, PhD


Abstract: New discoveries in Glioblastoma (GBM) biology have been made using genomics data.  Genomic markers are routinely integrated into clinical neurosurgical practice.  In this manuscript, we review fundamentals of genomics such as the differences between first, second, and third generation sequencing technology.  We also review the impact of single cell genomics in understanding the complex heterogenous GBM microenvironment.  Finally, we will discuss advances in epigenetics that have lent insights into treatment resistance. The integration of genomics into neuro-oncology clinical practice is routine and will continue to expand with the expansion of precision of medicine.  We provide a primer for clinicians.


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PATTERSON, John D; WONGSURAWAT, Thidathip; RODRIGUEZ, Analiz. A Glioblastoma Genomics Primer for Clinicians. Medical Research Archives, [S.l.], v. 8, n. 2, feb. 2020. ISSN 2375-1924. Available at: <https://journals.ke-i.org/mra/article/view/2034>. Date accessed: 04 apr. 2020. doi: https://doi.org/10.18103/mra.v8i2.2034.
Review Articles


1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330
2. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol. 2018;20(suppl_4):iv1-iv86. doi:10.1093/neuonc/noy131
3. Can T. Introduction to Bioinformatics. In: Methods in Molecular Biology (Clifton, N.J.). Vol 1107. ; 2014:51-71. doi:10.1007/978-1-62703-748-8_4
4. Louis DN, Perry A, Reifenberger • Guido, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. doi:10.1007/s00401-016-1545-1
5. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013;19(4):764-772. doi:10.1158/1078-0432.CCR-12-3002
6. Stephens ZD, Lee SY, Faghri F, et al. Big Data: Astronomical or Genomical? PLoS Biol. 2015;13(7):e1002195. doi:10.1371/journal.pbio.1002195
7. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820. doi:10.1007/s00401-016-1545-1
8. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 Mutations in Gliomas. N Engl J Med. 2009;360(8):765-773. doi:10.1056/NEJMoa0808710
9. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RGW, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015;372(26):2481-2498. doi:10.1056/NEJMoa1402121
10. Cohen A, Sato M, Aldape K, et al. DNA copy number analysis of Grade II–III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status. Acta Neuropathol Commun. 2015;3(1):34. doi:10.1186/s40478-015-0213-3
11. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474-478. doi:10.1038/nature10860
12. Ward PS, Patel J, Wise DR, et al. The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate. Cancer Cell. 2010;17(3):225-234. doi:10.1016/j.ccr.2010.01.020
13. Jalbert LE, Elkhaled A, Phillips JJ, et al. Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma. Sci Rep. 2017;7(1):44792. doi:10.1038/srep44792
14. Cheng W, Zhang C, Ren X, et al. Treatment strategy and IDH status improve nomogram validity in newly diagnosed GBM patients. Neuro Oncol. 2017;19(5):736-738. doi:10.1093/neuonc/nox012
15. Calvert AE, Chalastanis A, Wu Y, et al. Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell Rep. 2017;19(9):1858-1873. doi:10.1016/j.celrep.2017.05.014
16. Lee Y, Koh J, Kim S-I, et al. The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. Acta Neuropathol Commun. 2017;5(1):62. doi:10.1186/s40478-017-0465-1
17. Gessler F, Bernstock JD, Braczynski A, et al. Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas. Neurosurgery. 2018;84(1):190-197. doi:10.1093/neuros/nyy049
18. Wick W, Weller M, van den Bent M, et al. MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol. 2014;10(7):372-385. doi:10.1038/nrneurol.2014.100
19. Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916-926. doi:10.1016/S1470-2045(12)70265-6
20. Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707-715. doi:10.1016/S1470-2045(12)70164-X
21. Palmer JD, Bhamidipati D, Mehta M, et al. Treatment recommendations for elderly patients with newly diagnosed glioblastoma lack worldwide consensus. J Neurooncol. 2018;140(2):421-426. doi:10.1007/s11060-018-2969-3
22. Lipp ES, Healy P, Austin A, et al. MGMT: Immunohistochemical Detection in High-Grade Astrocytomas. J Neuropathol Exp Neurol. 2019;78(1):57-64. doi:10.1093/jnen/nly110
23. Mansouri A, Hachem LD, Mansouri S, et al. MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges. Neuro Oncol. September 2018. doi:10.1093/neuonc/noy132
24. Hicks MJ, Chiuchiolo MJ, Ballon D, et al. Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma. PLoS One. 2016;11(10):e0162978. doi:10.1371/journal.pone.0162978
25. Hegi ME, Rajakannu P, Weller M. Epidermal growth factor receptor. Curr Opin Neurol. 2012;25(6):774-779. doi:10.1097/WCO.0b013e328359b0bc
26. Tini P, Pastina P, Nardone V, et al. The combined EGFR protein expression analysis refines the prognostic value of the MGMT promoter methylation status in glioblastoma. Clin Neurol Neurosurg. 2016;149:15-21. doi:10.1016/j.clineuro.2016.07.023
27. Liu X, Wu G, Shan Y, Hartmann C, von Deimling A, Xing M. Highly prevalent TERT promoter mutations in bladder cancer and glioblastoma. Cell Cycle. 2013;12(10):1637-1638. doi:10.4161/cc.24662
28. Labussiere M, Boisselier B, Mokhtari K, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology. 2014;83(13):1200-1206. doi:10.1212/WNL.0000000000000814
29. Stichel D, Ebrahimi A, Reuss D, et al. Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma. Acta Neuropathol. 2018;136(5):793-803. doi:10.1007/s00401-018-1905-0
30. Shendure J, Balasubramanian S, Church GM, et al. DNA sequencing at 40: past, present and future. Nature. 2017;550(7676):345-353. doi:10.1038/nature24286
31. Koboldt DC, Steinberg KM, Larson DE, Wilson RK, Mardis ER. The next-generation sequencing revolution and its impact on genomics. Cell. 2013;155(1):27-38. doi:10.1016/j.cell.2013.09.006
32. van Dijk EL, Auger H, Jaszczyszyn Y, Thermes C. Ten years of next-generation sequencing technology. Trends Genet. 2014;30(9):418-426. doi:10.1016/j.tig.2014.07.001
33. McLendon R, Friedman A, Bigner D, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061-1068. doi:10.1038/nature07385
34. Ng K, Kim R, Kesari S, Carter B, Chen CC. Genomic profiling of glioblastoma: convergence of fundamental biologic tenets and novel insights. J Neurooncol. 2012;107(1):1-12. doi:10.1007/s11060-011-0714-2
35. Cho HJ, Zhao J, Jung SW, et al. Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma. Neuro Oncol. 2019;21(1):47-58. doi:10.1093/neuonc/noy123
36. Tang J, He D, Yang P, He J, Zhang Y. Genome-wide expression profiling of glioblastoma using a large combined cohort. Sci Rep. 2018;8(1):15104. doi:10.1038/s41598-018-33323-z
37. Brahm CG, Walenkamp AME, Van Linde ME, Verheul HMW, Fehrmann RSN. Identification of novel therapeutic targets in glioblastoma with functional genomic mRNA profiling. J Clin Oncol. 2017;35(15_suppl):2018-2018. doi:10.1200/JCO.2017.35.15_suppl.2018
38. Sahm F, Schrimpf D, Jones DTW, et al. Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol. 2016;131(6):903-910. doi:10.1007/s00401-015-1519-8
39. Movassaghi M, Shabihkhani M, Hojat SA, et al. Early experience with formalin-fixed paraffin-embedded (FFPE) based commercial clinical genomic profiling of gliomas-robust and informative with caveats. Exp Mol Pathol. 2017;103(1):87-93. doi:10.1016/j.yexmp.2017.06.006
40. Neilsen BK, Sleightholm R, McComb R, et al. Comprehensive genetic alteration profiling in primary and recurrent glioblastoma. J Neurooncol. December 2018:1-8. doi:10.1007/s11060-018-03070-2
41. Nørøxe DS, Skjøth-Rasmussen J, Brennum J, et al. GENE-50. GENOMIC PROFILING AND PRECISION MEDICINE IN GLIOBLASTOMA - A PROSPECTIVE STUDY. Neuro Oncol. 2017;19(suppl_6):vi103-vi103. doi:10.1093/neuonc/nox168.422
42. Sottoriva A, Spiteri I, Piccirillo SGM, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A. 2013;110(10):4009-4014. doi:10.1073/pnas.1219747110
43. Hambardzumyan D, Bergers G. Glioblastoma: Defining Tumor Niches. Trends in cancer. 2015;1(4):252-265. doi:10.1016/j.trecan.2015.10.009
44. Alves JM, Prieto T, Posada D. Multiregional Tumor Trees Are Not Phylogenies. Trends in cancer. 2017;3(8):546-550. doi:10.1016/j.trecan.2017.06.004
45. Tang F, Barbacioru C, Wang Y, et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods. 2009;6(5):377-382. doi:10.1038/nmeth.1315
46. Hwang B, Lee JH, Bang D. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med. 2018;50(8):96. doi:10.1038/s12276-018-0071-8
47. Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396-1401. doi:10.1126/science.1254257
48. Lee JH, Lee JE, Kahng JY, et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature. 2018;560(7717):243-247. doi:10.1038/s41586-018-0389-3
49. Darmanis S, Sloan SA, Croote D, et al. Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell Rep. 2017;21(5):1399-1410. doi:10.1016/j.celrep.2017.10.030
50. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2011;59(8):1169-1180. doi:10.1002/glia.21136
51. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20-27. doi:10.1038/nn.4185
52. Simmons GW, Pong WW, Emnett RJ, et al. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol. 2011;70(1):51-62. doi:10.1097/NEN.0b013e3182032d37
53. Gutmann DH, McLellan MD, Hussain I, et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res. 2013;23(3):431-439. doi:10.1101/gr.142604.112
54. Rossi ML, Hughes JT, Esiri MM, Coakham HB, Brownell DB. Immunohistological study of mononuclear cell infiltrate in malignant gliomas. Acta Neuropathol. 1987;74(3):269-277. doi:10.1007/bf00688191
55. Zhou W, Bao S. Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages. Cancers (Basel). 2014;6(2):723-740. doi:10.3390/cancers6020723
56. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 2006;8(3):261-279. doi:10.1215/15228517-2006-008
57. Kamran N, Kadiyala P, Saxena M, et al. Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy. Mol Ther. 2017;25(1):232-248. doi:10.1016/j.ymthe.2016.10.003
58. Szulzewsky F, Pelz A, Feng X, et al. Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PLoS One. 2015;10(2):e0116644. doi:10.1371/journal.pone.0116644
59. Thorsson V, Gibbs DL, Brown SD, et al. The Immune Landscape of Cancer. Immunity. 2018;48:812-830.e14. doi:10.1016/j.immuni.2018.03.023
60. Strauss J, Figg WD. Using epigenetic therapy to overcome chemotherapy resistance. Anticancer Res. 2016;36(1):1-4.
61. Klughammer J, Kiesel B, Roetzer T, et al. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nat Med. 2018;24(10):1611-1624. doi:10.1038/s41591-018-0156-x
62. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479-483. doi:10.1038/nature10866
63. Lapinska K, Faria G, McGonagle S, Macumber KM, Heerboth S, Sarkar S. Cancer Progenitor Cells: The Result of an Epigenetic Event? Anticancer Res. 2018;38(1):1-6. doi:10.21873/anticanres.12184
64. Chen J, Li Y, Yu T-S, et al. A restricted cell population propagates glioblastoma growth following chemotherapy. Nature. 2012;488(7412):522. doi:10.1038/NATURE11287
65. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-760. doi:10.1038/nature05236
66. Zhou D, Alver BM, Li S, et al. Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues. Genome Biol. 2018;19(1):43. doi:10.1186/s13059-018-1420-6
67. Pangeni RP, Zhang Z, Alvarez AA, et al. Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma. Epigenetics. 2018;13(4):432-448. doi:10.1080/15592294.2018.1469892
68. Aboulkheyr Es H, Montazeri L, Aref AR, Vosough M, Baharvand H. Personalized Cancer Medicine: An Organoid Approach. Trends Biotechnol. 2018;36(4):358-371. doi:10.1016/j.tibtech.2017.12.005
69. Ebrahimkhani S, Vafaee F, Hallal S, et al. Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis. NPJ Precis Oncol. 2018;2:28. doi:10.1038/s41698-018-0071-0
70. Miller AM, Shah RH, Pentsova EI, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature. 2019;565(7741):654-658. doi:10.1038/s41586-019-0882-3

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