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01-07-2020 | Glioma | Laboratory Investigation

Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma

Authors: Kevin Shee, Meagan Chambers, Edward G. Hughes, Damian A. Almiron, Sophie J. Deharvengt, Donald Green, Joel A. Lefferts, Angeline S. Andrew, William F. Hickey, Gregory J. Tsongalis

Published in: Journal of Neuro-Oncology | Issue 3/2020

Abstract

Introduction

Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS).

Methods

Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade.

Results

Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10^–8 and RFS p = 3.80 × 10^–7).

Conclusions

This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

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Schwartzbaum JA, et al. (2006). Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol, 2(9): p. 494–503; quiz 1 p following 516

Louis DN et al (2016) The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820PubMed

Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996CrossRefPubMed

Stupp R et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466PubMedCrossRef

Noushmehr H et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522PubMedPubMedCentralCrossRef

Verhaak RG 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):98–110PubMedPubMedCentralCrossRef

Sturm D et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22(4):425–437PubMedCrossRef

Zhao J, Ma W, Zhao H (2014) Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis. Neuro Oncol 16(1):103–112PubMedCrossRef

Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773PubMedPubMedCentralCrossRef

10.

Hegi ME et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003PubMedCrossRef

11.

Eckel-Passow JE et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372(26):2499–2508PubMedPubMedCentralCrossRef

12.

Jiao Y et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3(7):709–722PubMedPubMedCentralCrossRef

13.

Jakola AS et al (2012) Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 308(18):1881–1888PubMedCrossRef

14.

Aghi MK et al (2015) The role of surgery in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 125(3):503–530PubMedCrossRef

15.

Noorbakhsh A et al (2014) Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg 120(1):31–39PubMedCrossRef

16.

Keime-Guibert F et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356(15):1527–1535PubMedCrossRef

17.

Ryken TC et al (2015) The role of radiotherapy in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 125(3):551–583PubMedCrossRef

18.

van den Bent MJ et al (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366(9490):985–990PubMedCrossRef

19.

van den Bent MJ et al (2017) Interim results from the CATNON trial (EORTC study 26053–22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390(10103):1645–1653PubMedPubMedCentralCrossRef

20.

Perry JR et al (2017) Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 376(11):1027–1037PubMedCrossRef

21.

Tsongalis GJ et al (2014) Routine use of the Ion torrent ampliseq cancer hotspot panel for identification of clinically actionable somatic mutations. Clin Chem Lab Med 52(5):707–714PubMedCrossRef

22.

Gu Z, Eils R, Schlesner M (2016) Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32(18):2847–2849CrossRefPubMed

23.

Suzuki H et al (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47(5):458–468PubMedCrossRef

24.

Cancer Genome Atlas Research N, et al. (2015). Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas, N Engl J Med, 372(26): p. 2481–98

25.

Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477PubMedPubMedCentralCrossRef

26.

Bell EH et al (2018) Association of MGMT promoter methylation status with survival outcomes in patients with high-risk glioma treated with radiotherapy and temozolomide: an analysis from the nrg oncology/RTOG 0424 trial. JAMA Oncol 4(10):1405–1409PubMedCrossRef

27.

Cairncross JG et al (2014) Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol 32(8):783–790PubMedPubMedCentralCrossRef

28.

Buckner JC et al (2016) Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374(14):1344–1355PubMedPubMedCentralCrossRef

29.

Molenaar RJ et al (2017) Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open 7(6):e014961PubMedPubMedCentralCrossRef

30.

Sulkowski PL et al. (2017). 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity, Sci Transl Med, 9(375)

31.

Popovici-Muller J et al (2012) Discovery of the first potent inhibitors of mutant idh1 that lower tumor 2-HG in Vivo. ACS Med Chem Lett 3(10):850–855PubMedPubMedCentralCrossRef

32.

Clark KH et al (2013) 1p/19q testing has no significance in the workup of glioblastomas. Neuropathol Appl Neurobiol 39(6):706–717PubMedPubMedCentralCrossRef

33.

Ceccarelli M et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164(3):550–563PubMedPubMedCentralCrossRef

34.

Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25(3):304–317PubMedPubMedCentralCrossRef

35.

Canon J et al (2015) The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther 14(3):649–658PubMedCrossRef

36.

Bykov VJ et al (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288PubMedCrossRef

37.

Singh MM et al (2015) Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro Oncol 17(11):1463–1473PubMedPubMedCentralCrossRef

38.

Kottaridis PD, Gale RE, Linch DC (2003) Flt3 mutations and leukaemia. Br J Haematol 122(4):523–538PubMedCrossRef

39.

Nagel G et al (2017) Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol 96(12):1993–2003PubMedPubMedCentralCrossRef

40.

Grafone T et al (2012) An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev 6(1):e8PubMedPubMedCentralCrossRef

41.

Kiyoi H et al (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93(9):3074–3080PubMed

42.

Port M et al (2014) Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann Hematol 93(8):1279–1286PubMedCrossRef

43.

Essbach C et al (2013) Abundance of Flt3 and its ligand in astrocytic tumors. Onco Targets Ther 6:555–561PubMedPubMedCentral

44.

Bleeker FE et al (2014) Mutational profiling of kinases in glioblastoma. BMC Cancer 14:718PubMedPubMedCentralCrossRef

45.

Cerami E et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404PubMedCrossRef

46.

Fiedler W et al (2015) A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations. Br J Haematol 169(5):694–700PubMedCrossRef

47.

Muppidi MR et al (2015) Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 15(Suppl):S73–S79PubMedCrossRef

48.

Bastien JI, McNeill KA, Fine HA (2015) Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer 121(4):502–516PubMedCrossRef

49.

Neyns B et al (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 103(3):491–501PubMedCrossRef

Title: Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma
Authors: Kevin Shee
Meagan Chambers
Edward G. Hughes
Damian A. Almiron
Sophie J. Deharvengt
Donald Green
Joel A. Lefferts
Angeline S. Andrew
William F. Hickey
Gregory J. Tsongalis
Publication date: 01-07-2020
Publisher: Springer US
Keywords: Glioma
Glioma
Glioma
Published in: Journal of Neuro-Oncology / Issue 3/2020
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-020-03567-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma

Abstract

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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