Predictive biomarkers in adult gliomas: the present and the future

Purpose of review This review summarizes recent studies on the predictive value of molecular markers in adult gliomas, including 1p/19q codeletion, MGMT methylation, IDH mutation and markers identified using omics and next-generation sequencing studies. Recent findings The long-term results of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer trials in anaplastic oligodendroglial glioma have shown that the 1p/19q codeletion predicts an overall survival benefit from early PCV (procarbazine CCNU vincristine) chemotherapy. This benefit can also be predicted using gene expression-based molecular subtypes of gliomas while the predictive value of the IDH mutation in this context requires further study. In elderly patients with glioblastoma, the analysis of MGMT methylation status in two phase III trials suggests that this alteration may guide treatment decisions; however, this finding still needs confirmation in prospective studies. Omics and next-generation sequencing studies have identified additional potential predictive markers. In particular, IDH mutations, BRAF V600E mutations and FGFR gene fusions might predict efficacy of therapies targeted against these alterations. Summary Currently, the 1p/19q codeletion is the only well established predictive marker with clinical utility. However, it is likely that other molecular markers such as MGMT methylation, IDH mutation and those identified using omics and next-generation sequencing studies will further guide treatment decisions in adult gliomas.

[1]  K. Hoang-Xuan,et al.  Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Gary L. Gallia,et al.  TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal , 2013, Proceedings of the National Academy of Sciences.

[3]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[4]  K. Hoang-Xuan,et al.  Alpha‐internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy , 2011, Cancer.

[5]  Andrey Korshunov,et al.  Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations , 2012, Acta Neuropathologica.

[6]  Kirsten Schmieder,et al.  Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma , 2011, Acta Neuropathologica.

[7]  H. Zentgraf,et al.  Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody , 2011, Acta Neuropathologica.

[8]  Paul S Mischel,et al.  Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. , 2012, Cancer discovery.

[9]  R. Mirimanoff,et al.  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. , 2009, The Lancet. Oncology.

[10]  R. Guillevin,et al.  IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas , 2010, Neurology.

[11]  Olivier Delattre,et al.  Two types of chromosome 1p losses with opposite significance in gliomas , 2005, Annals of neurology.

[12]  K. Hoang-Xuan,et al.  Chromosome 1p loss evaluation in anaplastic oligodendrogliomas , 2008, Neuropathology : official journal of the Japanese Society of Neuropathology.

[13]  Jeffrey W. Clark,et al.  Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  A. Iafrate,et al.  Prospective, high-throughput molecular profiling of human gliomas , 2012, Journal of Neuro-Oncology.

[15]  Wei Wu,et al.  Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers , 2012, The Journal of pathology.

[16]  A. von Deimling,et al.  Highly prevalent TERT promoter mutations in bladder cancer and glioblastoma , 2013, Cell cycle.

[17]  R. Stallings,et al.  Loss of Chromosome 1p/19q in Oligodendroglial Tumors: Refinement of Chromosomal Critical Regions and Evaluation of Internexin Immunostaining as a Surrogate Marker , 2011, Journal of neuropathology and experimental neurology.

[18]  J. Uhm.  IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype , 2012 .

[19]  Jean-Yves Delattre,et al.  An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients , 2010, Molecular Cancer.

[20]  K. Hoang-Xuan,et al.  All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2 , 2010, Neurology.

[21]  K. Hoang-Xuan,et al.  Diagnostic and prognostic value of alpha internexin expression in a series of 409 gliomas. , 2011, European journal of cancer.

[22]  E. Shaw,et al.  Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  M. Delorenzi,et al.  MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status , 2012, Acta Neuropathologica.

[24]  D. Aisner,et al.  Epithelioid GBMs Show a High Percentage of BRAF V600E Mutation , 2013, The American journal of surgical pathology.

[25]  Jean-Yves Delattre,et al.  Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile , 2008, Molecular Cancer.

[26]  G. Reifenberger,et al.  Predictive impact of MGMT promoter methylation in glioblastoma of the elderly , 2012, International journal of cancer.

[27]  M. Weller,et al.  Prognostic Value of Three Different Methods of MGMT Promoter Methylation Analysis in a Prospective Trial on Newly Diagnosed Glioblastoma , 2012, PloS one.

[28]  C. Horbinski.  To BRAF or Not to BRAF: Is That Even a Question Anymore? , 2013, Journal of neuropathology and experimental neurology.

[29]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[30]  Fang Wang,et al.  An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells , 2013, Science.

[31]  Winand N M Dinjens,et al.  Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  R. Packer,et al.  Chemotherapy for low-grade gliomas , 1999, Child's Nervous System.

[33]  M. J. van den Bent,et al.  Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Andrew P. Stubbs,et al.  Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. , 2009, Cancer research.

[35]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[36]  M. Weller.  Assessing the MGMT status in glioblastoma: one step forward, two steps back? , 2013, Neuro-oncology.

[37]  R. Verhaak,et al.  Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation , 2012, Nature.

[38]  K. Hoang-Xuan,et al.  Primary brain tumours in adults , 2003, The Lancet.

[39]  C. Langford,et al.  Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. , 2010, Neuro-oncology.

[40]  R. McLendon,et al.  Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas , 2012, Oncotarget.

[41]  M. Sanson,et al.  KIAA1549‐BRAF Fusions and IDH Mutations Can Coexist in Diffuse Gliomas of Adults , 2012, Brain Pathology.

[42]  BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications , 2011, PloS one.

[43]  D. Aisner,et al.  Anaplastic PXA in adults: case series with clinicopathologic and molecular features , 2012, Journal of Neuro-Oncology.

[44]  K. Aldape,et al.  Initial treatment patterns over time for anaplastic oligodendroglial tumors. , 2012, Neuro-oncology.

[45]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[46]  M. J. van den Bent,et al.  MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Didier Frappaz,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. , 2012, The Lancet. Oncology.

[48]  M. Preusser,et al.  Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells , 2013, Acta Neuropathologica.

[49]  H Duffau,et al.  Temozolomide for low-grade gliomas , 2007, Neurology.

[50]  G. Reifenberger,et al.  Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. , 2012, The Lancet. Oncology.

[51]  D. Brat,et al.  Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma , 2012, Science.

[52]  Pieter Wesseling,et al.  A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951 , 2011, Clinical Cancer Research.

[53]  Walter Curran,et al.  Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  Yuchen Jiao,et al.  Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma , 2011, Science.

[55]  K. Hoang-Xuan,et al.  Primary brain tumours in adults , 2003, The Lancet.

[56]  G. Reifenberger,et al.  NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  E. Shaw,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. , 2006, Cancer research.

[58]  Denis Lacombe,et al.  Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  S. Berger,et al.  IDH mutation impairs histone demethylation and results in a block to cell differentiation , 2012, Nature.

[60]  Timothy A. Chan,et al.  Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma , 2012, Oncotarget.

[61]  M. Sanson,et al.  Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients , 2012, Cancer.

[62]  K. Ichimura,et al.  Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss , 2013, Acta Neuropathologica.

[63]  M. Chamberlain.  Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series , 2013, Journal of Neuro-Oncology.

[64]  Nickolay A. Khazanov,et al.  Identification of targetable FGFR gene fusions in diverse cancers. , 2013, Cancer discovery.