Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma.
Aged
Biomarkers, Tumor
/ genetics
Brain Neoplasms
/ genetics
Cohort Studies
Combined Modality Therapy
DNA Methylation
Follow-Up Studies
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioma
/ genetics
Humans
Middle Aged
Mutation
Prognosis
Survival Rate
fms-Like Tyrosine Kinase 3
/ genetics
Glioma
Molecular profiles
Next generation sequencing
Targeted therapy
Journal
Journal of neuro-oncology
ISSN: 1573-7373
Titre abrégé: J Neurooncol
Pays: United States
ID NLM: 8309335
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
01
05
2020
accepted:
16
06
2020
pubmed:
26
6
2020
medline:
8
6
2021
entrez:
26
6
2020
Statut:
ppublish
Résumé
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). 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. 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 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.
Identifiants
pubmed: 32583303
doi: 10.1007/s11060-020-03567-9
pii: 10.1007/s11060-020-03567-9
doi:
Substances chimiques
Biomarkers, Tumor
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
473-480Références
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):803–820
pubmed: 27157931
pmcid: 27157931
Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996
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):459–466
pubmed: 19269895
Noushmehr H et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522
pubmed: 20399149
pmcid: 2872684
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):98–110
pubmed: 20129251
pmcid: 20129251
Sturm D et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22(4):425–437
pubmed: 23079654
Zhao J, Ma W, Zhao H (2014) Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis. Neuro Oncol 16(1):103–112
pubmed: 24311641
Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773
pubmed: 19228619
pmcid: 2820383
Hegi ME et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003
pubmed: 15758010
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):2499–2508
pubmed: 26061753
pmcid: 26061753
Jiao Y et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3(7):709–722
pubmed: 22869205
pmcid: 3443254
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):1881–1888
pubmed: 23099483
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):503–530
pubmed: 26530265
Noorbakhsh A et al (2014) Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg 120(1):31–39
pubmed: 24205904
Keime-Guibert F et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356(15):1527–1535
pubmed: 17429084
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):551–583
pubmed: 26530266
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):985–990
pubmed: 16168780
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):1645–1653
pubmed: 28801186
pmcid: 5806535
Perry JR et al (2017) Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 376(11):1027–1037
pubmed: 28296618
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):707–714
pubmed: 24334431
Gu Z, Eils R, Schlesner M (2016) Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32(18):2847–2849
Suzuki H et al (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47(5):458–468
pubmed: 25848751
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
Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477
pubmed: 24120142
pmcid: 3910500
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):1405–1409
pubmed: 29955793
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):783–790
pubmed: 24516018
pmcid: 3940537
Buckner JC et al (2016) Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374(14):1344–1355
pubmed: 27050206
pmcid: 5170873
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):e014961
pubmed: 28601826
pmcid: 5541450
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)
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):850–855
pubmed: 24900389
pmcid: 4025665
Clark KH et al (2013) 1p/19q testing has no significance in the workup of glioblastomas. Neuropathol Appl Neurobiol 39(6):706–717
pubmed: 23363074
pmcid: 4095883
Ceccarelli M et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164(3):550–563
pubmed: 26824661
pmcid: 4754110
Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25(3):304–317
pubmed: 24651012
pmcid: 3970583
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):649–658
pubmed: 25567130
Bykov VJ et al (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288
pubmed: 11875500
Singh MM et al (2015) Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro Oncol 17(11):1463–1473
pubmed: 25795306
pmcid: 4648298
Kottaridis PD, Gale RE, Linch DC (2003) Flt3 mutations and leukaemia. Br J Haematol 122(4):523–538
pubmed: 12899708
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):1993–2003
pubmed: 29090343
pmcid: 5691091
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):e8
pubmed: 25992210
pmcid: 4419636
Kiyoi H et al (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93(9):3074–3080
pubmed: 10216104
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):1279–1286
pubmed: 24801015
Essbach C et al (2013) Abundance of Flt3 and its ligand in astrocytic tumors. Onco Targets Ther 6:555–561
pubmed: 23737671
pmcid: 3667997
Bleeker FE et al (2014) Mutational profiling of kinases in glioblastoma. BMC Cancer 14:718
pubmed: 25256166
pmcid: 4192443
Cerami E et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404
pubmed: 22588877
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):694–700
pubmed: 25818407
Muppidi MR et al (2015) Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 15(Suppl):S73–S79
pubmed: 26297284
Bastien JI, McNeill KA, Fine HA (2015) Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer 121(4):502–516
pubmed: 25250735
Neyns B et al (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 103(3):491–501
pubmed: 20872043