Beyond the World Health Organization grading of infiltrating gliomas: advances in the molecular genetics of glioma classification

Abstract

Background: Traditional classification of diffuse infiltrating gliomas (DIGs) as World Health Organization (WHO) grades II-IV is based on histological features of a heterogeneous population of tumors with varying prognoses and treatments. Over the last decade, research efforts have resulted in a better understanding of the molecular basis of glioma formation as well as the genetic alterations commonly identified in diffuse gliomas.

Methods: A systematic review of the current literature related to advances in molecular phenotypes, mutations, and genomic analysis of gliomas was carried out using a PubMed search for these key terms. Data was studied and synthesized to generate a comprehensive review of glioma subclassification.

Results: This new data helps supplement the existing WHO grading scale by subtyping gliomas into specific molecular groups. The emerging molecular profile of diffuse gliomas includes the studies of gene expression and DNA methylation in different glioma subtypes. The discovery of novel mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) provides new biomarkers as points of stratification of gliomas based on prognosis and treatment response. Gliomas that harbor CpG island hypermethylator phenotypes constitute a subtype of glioma with improved survival. The difficulty of classifying oligodendroglial lineage of tumors can be aided with identification of 1p/19q codeletion. Glioblastomas (GBMs) previously described as primary or secondary can now be divided based on gene expression into proneural, mesenchymal, and classical subtypes and the identification of mutations in the promoter region of the telomerase reverse transcriptase (TERTp) have been correlated with poor prognosis in GBMs.

Conclusions: Incorporation of new molecular and genomic changes into the existing WHO grading of DIGs may provide better patient prognostication as well as advance the development of patient-specific treatments and clinical trials.

Keywords: Biological markers; genomics; glioma; mutations; prognosis.

Figure 1

IDH1 IHC staining of an AA at 40×. (A) H&E stain of AA; (B) IDH1 R132H IHC of AA shows high levels of intracellular mutant IDH protein in neoplastic cells. IDH1, isocitrate dehydrogenase 1; IHC, immunohistochemical; AA, anaplastic astrocytoma; H&E, hematoxylin and eosin.

Figure 2

Virtual karyotype generated from a SNP array by chromosome analysis suite freeware. (A) Chromosome analysis suite virtual karyotype of a patient with GBM who had tissue sent for SNP array analysis. Classical findings of Chr 10 loss and 7 gain are identified with novel focal amplifications of Chr 12 (B) of GLI1 and (C) CDK4. This unique genomic profile is the signature of a classical GBM with new therapeutic targets in GLI/CDK4/6. Similar analysis can be carried out on high grade gliomas to help with diagnosis when histology is equivocal and aid in determining prognosis. GBM, glioblastomas.

Figure 3

NCBI BLAST readout for a portion of the genome associated with unique amplifications identified in chromosome analysis. Data identified in chromosome analysis can be further interpreted with aid of online resources to aid in the discovery of new mutations and subclass of gliomas. In the above NCBI query of the amplified portion of Chr 12 identified in prior patient, we are able to view all genes that may be affected as a result of the mutation and determine which genes are of known clinical significance and which remain to be studied.

Figure 4

ATRX IHC staining of an AA at 40×. (A) H&E stain of gliomas; (B) ATRX staining of AA shows absence of normal ATRX in neoplastic cells, while normal staining (brown) can be seen in glial and endothelial cells. IHC, immunohistochemical; AA, anaplastic astrocytoma; H&E, hematoxylin and eosin.

Figure 5

p53 IHC staining of an AA at 40×. (A) H&E stain of high grade gliomas; (B) p53 stain for aggregation of mutant p53 protein. IHC, immunohistochemical; AA, anaplastic astrocytoma; H&E, hematoxylin and eosin.

Figure 6

Hypothesized pathways of gliomagenesis based on recent TCGA data. Hypothesized pathways of gliomagenesis based on TCGA data leading to the formation of subtypes of GBM: mesenchymal, classical, proneural and GBM-O. GBM, glioblastomas; IDH, isocitrate dehydrogenase; TCGA, The Cancer Genome Atlas.