Molecular Pathology Tools for Glioma Grading

Gliomas have been extensively characterized by cyto-genetic, molecular cytogenetic, and molecular genetic methods (reviewed in References 3, 5, and 6). Figure 27-1

Table 27-1. Molecular Markers of Gliomas

Marker

Indication

Markers Currently Entering Clinical Practice

1p/19q deletion testing

Oligodendroglioma diagnosis and

prognosis

Prediction of oligodendroglioma

therapeutic response

Markers with Clinical Potential

EGFR amplification

Small cell GBM diagnosis and

(overexpression)

differentiation from

oligodendroglioma

Prediction of high-grade glioma

therapeutic response to novel

EGFR pathway inhibitors

Chromosome 10 loss/

Prognosis of anaplastic astrocytomas

PTEN mutation

Subclassification of mixed

oligoastrocytomas

TP53 mutation

Prognosis of anaplastic astrocytomas

1p/19q deletion testing

Subclassification of mixed

oligoastrocytomas

summarizes the major genetic alterations found in diffuse gliomas. Some of these alterations are highly correlated with the grade of gliomas, especially for astrocytic tumors.

Several genetic alterations have been associated with GBM, especially primary GBM. These alterations include loss of chromosome 10, mutation of the PTEN gene, and amplification of the EGFR gene with resulting over expression of the EGFR protein. While the clinical use of these markers has not been completely validated, there is growing evidence that they may prove useful as a molecular adjunct for glioma grading. The presence of EGFR amplification, chromosome 10 loss, or PTEN mutation, or some combination of the three, in a glioma indicates that the tumor is likely a GBM. Importantly, a small but significant proportion of tumors with the histologic features of AA have one or more of these alterations.7-11 It is reasonable to hypothesize that since patients with GBM have a poor prognosis, then patients whose AA shares molecular characteristics with GBM also may have a poor survival.

A recent Mayo Clinic/North Central Cancer Treatment Group (NCCTG) study indicated that A A with chromosome 10 loss or PTEN mutation behaves like GBM.8 The median survival of patients with AA and chromosome 10 loss or PTEN mutation was approximately 4 months, a survival worse than that of patients with GBM (who had a median survival of approximately 12 months). The median survival of patients whose AA lacked these alterations was 34 months. This difference in survival was statistically significant even after adjustment for patient age, performance score, and extent of resection, all of which are important prognostic variables for patients with gliomas. Importantly, the patient survival for GBM with and without chromosome 10 loss or PTEN mutations was very similar.8 It is possible that sampling bias (in terms of the tissue available for histologic and molecular analysis) may have accounted for the differences. However, sampling bias is a difficult problem to overcome in routine clinical practice, and molecular testing for chromosome 10 loss or PTEN mutations in a sample of a tumor with the features of an AA indicates that the tumor may be a GBM.

Interestingly, the Mayo Clinic/NCCTG study did not show that AA with EGFR amplification behaved like GBM.8 However, careful stratification indicated that AA and GBM with EGFR amplification in young patients (i.e., less than 40 years old) progress much faster than AA and GBM

TP53 mutation PDGFR overexpression 22q loss

TP53 mutation PDGFR overexpression 22q loss

Figure 27-1. Possible genetic pathways of diffuse glioma formation and progression (modified from References 5 and 6). Histologic classification is based on current WHO guidelines.2 Although the molecular genetic evidence is increasing, it is not widely accepted that anaplastic oligodendroglioma progresses to GBM (dashed arrow).

Chromosome 10 loss

PTEN mutation PDGFR amplification

Chromosome 10 loss

PTEN mutation PDGFR amplification

Figure 27-1. Possible genetic pathways of diffuse glioma formation and progression (modified from References 5 and 6). Histologic classification is based on current WHO guidelines.2 Although the molecular genetic evidence is increasing, it is not widely accepted that anaplastic oligodendroglioma progresses to GBM (dashed arrow).

without EGFR amplification in this age group.8 Conversely, AA and GBM with EGFR amplification in older patients (i.e., greater than 60 years old) had a better prognosis than those without this alteration. Importantly, this result has been confirmed by another group.12 These differences in age-related prognosis may reflect the different biology of primary and secondary high-grade astrocytic tumors. EGFR amplification is accompanied by sequence alterations in the EGFR gene (reviewed in Reference 13). The most common alteration is deletion of exons 2 to 7 (the EGFRvIII variant), which generates an EGFR protein that is active independently of ligand binding. However, there are several other amplified and mutated EGFR proteins (for example, the C958 variant is truncated after amino acid 958), some of which remain ligand dependent. Current translational studies are investigating the prevalence of these different amplified and mutated EGFR variants in primary and secondary GBM, and in GBM from patients of different ages.14

TP53 mutations are found in about half of astrocytomas and AA. About one quarter of GBM have been observed to have TP53 mutations, and these tumors often have the clinical presentation of a secondary GBM. Since TP53 alterations usually are associated with low-grade tumors, it has been hypothesized that high-grade astrocytic tumors with TP53 alterations may have a better prognosis. Except for the rare giant cell and gemistocytic variants (in which TP53 mutations are especially prevalent15,16), TP53 alterations do not seem to predict survival for GBM.17-20 However, in the Mayo Clinic/NCCTG series, the median survival of patients with AA and TP53 mutations was 5 years.8 This survival was significantly longer than those without TP53 mutations.8

Although PTEN, chromosome 10, TP53, and EGFR alterations have been found to be correlated with clinical grade and thus with patient prognosis, they have yet to be routinely used in clinical practice for two reasons. First, the studies require broader validation. Second, and more importantly, the presence or absence of such alterations does not currently change the clinical management of these patients. High-grade glioma trials designed to specifically evaluate the clinical usefulness of these markers are needed to move these molecular markers into clinical practice.

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