Molecular Markers and Clinical Implications in Glioma Treatment

Yakup DÜZKÖPRÜa, Umut DEMİRCİb

aAksaray Training and Research Hospital, Clinic of Medical Oncology, Aksaray, Türkiye
bMemorial Ankara Hospital, Clinic of Medical Oncology, Ankara, Türkiye

Düzköprü Y, Demirci U. Molecular markers and clinical implications in glioma treatment. In: Uğur HÇ, Bayatlı E, eds. Glial Tumours: Expectations from Today-Promises of the Future. 1st ed. Ankara: Türkiye Klinikleri; 2024. p.58-62.

ABSTRACT

Gliomas, primarily originating from astrocytes and oligodendroglial cells, constitute over 80% of CNS malignancies. Advances in molecular biology have led to a refined classification of gliomas, incorporating genetic markers such as IDH mutations, 1p/19q codeletion, MGMT methylation, and oth- ers. These markers significantly influence prognosis and treatment strategies. IDH mutations and 1p/19q codeletion are associated with better outcomes, while alterations like EGFR amplification and TERT promoter mutations typically indicate a poorer prognosis. Targeted therapies, including IDH inhibitors, and immunotherapies, such as PD-1 inhibitors, are being explored to improve survival rates. Despite progress, high-grade gliomas often recur, posing treatment challenges. Molecular profiling is crucial for personalized treatment approaches, aiming to enhance patient outcomes in glioma therapy.

Keywords: Astrocytoma; glioma; molecular targeted therapy; molecular typing; brain neoplasms

Referanslar

  1. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014;16(7):896-913. [Crossref]  [PubMed]  [PMC]
  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. [Crossref]  [PubMed]
  3. Wu A, Lim M. The Challenges and Future of Immunotherapy for Gliomas. Cancer J. 2021;27(5):371-8. [Crossref]  [PubMed]
  4. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-51. [Crossref]  [PubMed]  [PMC]
  5. Bruford EA, Braschi B, Denny P, Jones TEM, Seal RL, Tweedie S. Guidelines for human gene nomenclature. Nat Genet. 2020;52(8):754-8. [Crossref]  [PubMed]  [PMC]
  6. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21(Suppl 5):v1-v100. [Crossref]  [PubMed]  [PMC]
  7. Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 2020;87:102029. [Crossref]  [PubMed]
  8. Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, et al. Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer. 2022;21(1):39. [Crossref]  [PubMed]  [PMC]
  9. Felistia Y, Wen PY. Molecular Profiling and Targeted Therapies in Gliomas. Curr Neurol Neurosci Rep. 2023;23(10):627-36. [Crossref]  [PubMed]
  10. Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 2020;22(8):1073-113. [PubMed]
  11. Karschnia P, Young JS, Dono A, Hani L, Sciortino T, Bruno F, et al. Prognostic validation of a new classification system for extent of resection in glioblastoma: A report of the RANO resect group. Neuro Oncol. 2023;25(5):940-54. [PMC]
  12. 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):987-96. [Crossref]  [PubMed]
  13. 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):1807-12. [Crossref]  [PubMed]  [PMC]
  14. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474-8. [Crossref]  [PubMed]  [PMC]
  15. Sabha N, Knobbe CB, Maganti M, Al Omar S, Bernstein M, Cairns R, et al. Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas. Neuro Oncol. 2014;16(7):914-23. [Crossref]  [PubMed]  [PMC]
  16. Sledzinska P, Bebyn MG, Furtak J, Kowalewski J, Lewandowska MA. Prognostic and Predictive Biomarkers in Gliomas. Int J Mol Sci. 2021;22(19):10373. [Crossref]  [PubMed]  [PMC]
  17. Dai Y, Ning X, Han G, Li W. Assessment of the Association between Isocitrate Dehydrogenase 1 Mutation and Mortality Risk of Glioblastoma Patients. Mol Neurobiol. 2016;53(3):1501-8. [Crossref]  [PubMed]
  18. Zou P, Xu H, Chen P, Yan Q, Zhao L, Zhao P, et al. IDH1/IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PLoS One. 2013;8(7):e68782. [Crossref]  [PubMed]  [PMC]
  19. Mellinghoff IK, Ellingson BM, Touat M, Maher E, De La Fuente MI, Holdhoff M, et al. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma. J Clin Oncol. 2020;38(29):3398-406. [Crossref]  [PubMed]  [PMC]
  20. Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023;389(7):589-601. [Crossref]  [PubMed]  [PMC]
  21. Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015;372(26):2481-98. [Crossref]  [PubMed]  [PMC]
  22. Griffin CA, Burger P, Morsberger L, Yonescu R, Swierczynski S, Weingart JD, et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol. 2006;65(10):988-94. [Crossref]  [PubMed]
  23. Hu X, Martinez-Ledesma E, Zheng S, Kim H, Barthel F, Jiang T, et al. Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. Neuro Oncol. 2017;19(6):786-95. [Crossref]  [PubMed]  [PMC]
  24. Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006; 66(20):9852-61. [Crossref]  [PubMed]
  25. Brigliadori G, Foca F, Dall'Agata M, Rengucci C, Melegari E, Cerasoli S, et al. Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma. J Neurooncol. 2016;128(2):333-9. [Crossref]  [PubMed]
  26. 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. [Crossref]  [PubMed]
  27. 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. [Crossref]  [PubMed]  [PMC]
  28. 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. [PubMed]
  29. Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV". Acta Neuropathol. 2018;136(5):805-10. [Crossref]  [PubMed]  [PMC]
  30. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2): 462-77. [PMC]
  31. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016;7(22): 33440-50. [Crossref]  [PubMed]  [PMC]
  32. Rosenthal M, Clement PM, Campone M, Gil-Gil MJ, DeGroot J, Chinot O, et al. Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study. ESMO Open. 2020;5(4):e000672. [Crossref]  [PubMed]  [PMC]
  33. Van Den Bent M, Eoli M, Sepulveda JM, Smits M, Walenkamp A, Frenel JS, et al. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro Oncol. 2020;22(5):684-93. [Crossref]  [PubMed]  [PMC]
  34. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 2012;8(7):e1002772. [Crossref]  [PubMed]  [PMC]
  35. 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):1194-203. [Crossref]  [PubMed]  [PMC]
  36. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013;126(2):267-76. [Crossref]  [PubMed]
  37. Shu C, Wang Q, Yan X, Wang J. The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI-derived and clinical features, predict adult primary glioblastoma survival. Cancer Med. 2018;7(8):3704-12. [Crossref]  [PubMed]  [PMC]
  38. Vuong HG, Altibi AMA, Duong UNP, Ngo HTT, Pham TQ, Chan AK, et al. TERT promoter mutation and its interaction with IDH mutations in glioma: Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups-A meta-analysis of aggregate data. Crit Rev Oncol Hematol. 2017;120:1-9. [Crossref]  [PubMed]
  39. Yuan Y, Qi C, Maling G, Xiang W, Yanhui L, Ruofei L, et al. TERT mutation in glioma: Frequency, prognosis and risk. J Clin Neurosci. 2016;26:57-62. [Crossref]  [PubMed]
  40. Lu VM, O'Connor KP, Shah AH, Eichberg DG, Luther EM, Komotar RJ, et al. The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature. J Neurooncol. 2020;148(2):221-9. [Crossref]  [PubMed]
  41. Stichel D, Ebrahimi A, Reuss D, Schrimpf D, Ono T, Shirahata M, 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. [Crossref]  [PubMed]
  42. Richard S, Tachon G, Milin S, Wager M, Karayan-Tapon L. Dual MGMT inactivation by promoter hypermethylation and loss of the long arm of chromosome 10 in glioblastoma. Cancer Med. 2020;9(17):6344-53. [Crossref]  [PubMed]  [PMC]
  43. Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):1307-16. [Crossref]  [PubMed]
  44. Blay JY, Cropet C, Mansard S, Loriot Y, De La Fouchardiere C, Haroche J, et al. Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAF(V600)-mutated melanoma. ESMO Open. 2023;8(6):102038. [Crossref]  [PubMed]  [PMC]
  45. Wen PY, Burgess P, Ilankumaran P, Subbiah V. ROAR trial: which treatment is effective after progression? - Authors' reply. Lancet Oncol. 2022;23(3):e94. [Crossref]  [PubMed]
  46. Blumenthal DT, Yalon M, Vainer GW, Lossos A, Yust S, Tzach L, et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J Neurooncol. 2016;129(3):453-60. [Crossref]  [PubMed]
  47. Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020; 6(7):1-8. [Crossref]  [PubMed]  [PMC]
  48. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477-86. [Crossref]  [PubMed]  [PMC]