IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma

The current World Health Organization (WHO) classification of human gliomas is mainly based on morphology. However, it has limitations in prognostic prediction. We examined whether combining isocitrate dehydrogenase (IDH) 1/2 mutation status with the Ki-67 labeling index would improve the definition of prognostically distinct entities. We investigated the correlation of Ki-67 expression with IDH1/2 mutation status and their impact on clinical outcome in 703 gliomas. Low Ki-67 expression closely overlapped with IDH1/2 mutation in our cohort (P < 0.0001). Patients with IDH1/2 mutation survived significantly longer than patients with wild-type IDH1/2 did (P < 0.0001); higher Ki-67 expression was associated with shorter progression-free survival and overall survival (OS) (P < 0.0001). IDH1/2 combined with Ki-67 was used to re-classify glioma patients into five groups. IDH1/2 mutant patients with low and moderate Ki-67 expression (Group1) had the best prognosis, whereas patients with wild-type IDH1/2 and high Ki-67 expression (Group5) had the worst prognosis (Median OS = 1527 vs. 355 days, P < 0.0001). To summarize, our new classification model distinguishes biologically distinct subgroups and provides prognostic information regardless of the conventional WHO grade. Classification based on IDH1/2 mutation status and Ki-67 expression level could be more convenient for clinical application and guide personalized treatment in malignant gliomas.

[1]  C. Horbinski.  What do we know about IDH1/2 mutations so far, and how do we use it? , 2013, Acta Neuropathologica.

[2]  A. Peraud,et al.  IDH1 mutations in grade II astrocytomas are associated with unfavorable progression‐free survival and prolonged postrecurrence survival , 2012, Cancer.

[3]  J.,et al.  The New England Journal of Medicine , 2012 .

[4]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[5]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[6]  N. Kanomata,et al.  Assessment of the Ki67 labeling index: a Japanese validation ring study , 2014, Breast Cancer.

[7]  T. Jiang,et al.  Gene expression profiling reveals Ki-67 associated proliferation signature in human glioblastoma. , 2011, Chinese medical journal.

[8]  W. Yung,et al.  IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. , 2013, Neuro-oncology.

[9]  Michael Weller,et al.  Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. , 2012, Neuro-oncology.

[10]  G. Reifenberger,et al.  Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas , 2010, Acta Neuropathologica.

[11]  Caterina Giannini,et al.  Assessment and Prognostic Significance of Mitotic Index Using the Mitosis Marker Phospho-histone H3 in Low and Intermediate-grade Infiltrating Astrocytomas , 2006, The American journal of surgical pathology.

[12]  J. Huse,et al.  IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma , 2012, Clinical Cancer Research.

[13]  A. von Deimling,et al.  Clonal Analysis in Recurrent Astrocytic, Oligoastrocytic and Oligodendroglial Tumors Implicates IDH1- Mutation as Common Tumor Initiating Event , 2012, PloS one.

[14]  K. Aldape,et al.  IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas , 2015, Acta Neuropathologica.

[15]  Lei Wang,et al.  Correlation of IDH1 Mutation with Clinicopathologic Factors and Prognosis in Primary Glioblastoma: A Report of 118 Patients from China , 2012, PloS one.

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

[17]  Frank M. Sacks,et al.  IDH 1 and IDH 2 Mutations in Gliomas , 2009 .

[18]  J. Uhm.  IDH1 and IDH2 Mutations in Gliomas , 2009 .

[19]  T. Jiang,et al.  Correlation of IDH1/2 mutation with clinicopathologic factors and prognosis in anaplastic gliomas: a report of 203 patients from China , 2013, Journal of Cancer Research and Clinical Oncology.

[20]  T. Jiang,et al.  Identifying Ki-67 specific miRNA–mRNA interactions in malignant astrocytomas , 2013, Neuroscience Letters.

[21]  A. Viale,et al.  IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype , 2012, Nature.

[22]  T. Jiang,et al.  ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples , 2014, Oncotarget.

[23]  L. Liau,et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate , 2009, Nature.