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1P/19Q CODELETION

Combined loss of the short arm of chromosome 1 and the

long of chromosome 19 is a hallmark genetic feature of

oligodendrogliomas (20). 1p and 19q codeleted tumors

carry a much better prognosis in comparison to similar grade

tumors without codeletion. A single deletion of either 1p

or 19q does not carry the same prognostic significance and

may in fact represent poorer prognosis. Histological evidence

of an oligodendroglioma is almost always coexistent with

IDH1/2

mutations (21). Cairncross et al. in 1998 reported

1p/19q-codeletion status to be a predictive biomarker and

prognostic with longer overall survival in anaplastic oligo-

dendroglioma patients (22). RTOG 9402 (23) (neoadju-

vant chemotherapy) and EORTC 26951 (24) (post–radiation

chemotherapy) both utilizing combination chemotherapy

of procarbazine, CCNU and vincristine showed doubling of

survival in patients treated with initial chemoradiation versus

radiation therapy alone, thereby confirming the predictive

role of this molecular marker. RTOG 9802 (3) using a similar

approach in high-risk grade II tumors did not have a suffi-

ciently large enough sample size to measure the differential

effect, although the European study EORTC 22033 did report

best outcomes in

IDH

-mutant and 1p/19q-codeleted tumors

(15). Less responsiveness of the

IDH

-mutant non-codeleted

tumor patients to chemotherapy alone highly suggests the

predictive role of this biomarker. 1p/19q-codeletion testing

can be done either by fluorescent in-situ hybridization,

polymerase chain reaction (PCR)-based microsatellite anal-

ysis, or the use of newer methods such as microarrays, all of

which require sufficient time and are usually not available at

the time of diagnosis. A newer biomarker, mutated ATRX, is

almost always mutually exclusive of 1p/19q-codeletion (25)

and can be interrogated quickly through immunohistochem-

istry testing (IHC loss indicating presence of the inactivating

mutation). This testing is increasingly becoming part of the

diagnostic algorithm, as indicated in the updated 2016 WHO

classification (Figure 1).

MGMT PROMOTER METHYLATION

Epigenetic silencing of the MGMT (O6-methylguanine–DNA

methyltransferase) gene by promoter methylation has been

associated with longer overall survival in patients with newly

diagnosed glioblastoma treated with alkylator chemotherapy,

especially in the elderly population (26,27), which resulted

in MGMT testing as standard of care in this patient popula-

tion. In the exploratory analysis of patients with anaplastic

astrocytoma in the NOA-4 trial, MGMT promoter methylation

predicted benefit to alkylator chemotherapy only in patients

with

IDH

-wildtype but not in

IDH

-mutant tumors (14). This

will need further testing in prospective clinical trials. The

technique of testing MGMT in tumor specimens has been

an issue of ongoing debate. In clinical practice DNA-based

methylation-specific PCR (MS-PCR) is the most commonly

used test. MGMT protein testing by IHC, real time PCR, meth-

ylation specific pyrosequencing, methylation-specific multi-

plex ligation–dependent probe amplification, and mRNA

expression testing are some of the other MGMT analysis

methods. There is currently a lack of consensus regarding the

most optimal method and the cut-off values used for each

testing, which makes interpretation of clinical studies diffi-

cult. Another challenge is the heterogeneity of tumor spec-

imens, especially when biopsies alone are available which

results in variable frequency of methylation thereby making

the final determination of methylation difficult. Approxi-

mately 15% of patients treated with temozolomide survived

2 years or more despite having MGMT nonmethylated tumors

(28). This suggests other mechanisms that may be respon-

sible for improved response to treatment. One such mecha-

nism that has been proposed is the presence of the T allele

rs16906252 T genotype, which has been shown to be asso-

ciated with better survival, irrespective of tumor methylation

status (29). Although a large majority of recurrent GBM tumors

have shown to have retained the MGMT methylation status,

their preferential response to chemotherapy in this setting

has not been statistically proven (30-33). MGMT methylated

status has been significantly correlated (30%) with the inci-

dence of pseudoprogression (34) which is believed to reflect

increased glioma killing effects of treatment. It is usually seen

within the first 3 months of chemoradiotherapy treatment,

but may be seen up to 6 months making interpretation of

followup MRI scans complicated.

EGFR MUTATION

Epidermal growth factor receptor (EGFR) is a 170-kDa trans-

membrane glycoprotein with an extracellular ligand binding

domain and a cytoplasmic domain containing a tyrosine

kinase. It is associated with a more aggressive phenotype

and is overexpressed in the small cell variant of glioblas-

toma (35,36). Although preclinical results suggested activity

of monotherapy with tyrosine kinase inhibitors (37), the

clinical trials using this mechanism failed to show ther-

apeutic activity (38) suggesting that alternative kinase

signaling pathways may be involved or there is heteroge-

neous expression of EGFR (39). An in-frame deletion of 801

base pairs in the extracellular domain of EGFR gene defines

EGFRvIII, a genetic variant of the EGFR gene that is associated

with poor survival (40), but this has been debated in some

other studies (41). EGFRvIII has been reported in about 50%

of EGFR-amplified glioblastomas and in 20–30% of primary

glioblastoma (42). A targeted peptide vaccine against

EGFRvIII conjugated with keyhole limpet hemocyanin (KLH)

paved the way for exploring immunotherapy as a treatment

[REV. MED. CLIN. CONDES - 2017; 28(3) 343-351]