Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective

Glioblastoma (World Health Organization [WHO] grade IV) is the most common intrinsic brain tumor. The prognosis for patients suffering from this disease remains dismal. Age in particular is a strong negative predictor for survival, resulting in a population-based median survival of elderly patients (ie, >65 y) of 70% of WHO grades II and III gliomas and secondary glioblastomas.13 In primary glioblastomas, IDH mutations are rare. Importantly, IDH mutations are associated with a significantly longer survival time compared with IDH wild-type tumors. Among grades III and IV gliomas pooled, IDH has a stronger prognostic impact than WHO grade. In the same study, the authors also found that in patients age ≥60 years with anaplastic astrocytoma and glioblastoma, IDH1 mutation was found in only 7.5% of the patients (11/146).14 Analysis of the glioblastoma epigenome revealed a distinct hypermethylator phenotype, the glioma cytosine–phosphate–guanine (CpG) island methylator phenotype (G-CIMP), which confers a good prognosis.15 Tumors positive for G-CIMP usually harbor IDH mutations, hence they are common among grades II and III gliomas and rare in primary glioblastomas. Genome- and epigenome-wide analyses of glioblastoma samples further revealed frequent mutations in the histone 3.3 gene (H3F3A) at K27 or G34.16 Just like IDH mutations, both K27M and G34R/V mutations are associated with a distinct epigenetic signature and possibly cell of origin each. In this study, tumors carrying G34 mutations show a favorable clinical course.17 Importantly, H3F3A and IDH mutations are mutually exclusive, suggesting that mutations in either of these genes represent different gliomagenic pathways. While the aforementioned alterations are prognostic, Agnihotri et al18 recently reported on epigenetic inactivation of alkylpurine DNA N-glycosylase (APNG) as a predictive biomarker for benefit from TMZ treatment. APNG is a DNA base excision repair enzyme, which catalyzes removal of N3-methyladenine and N7-methylguanine from DNA, both of which can be caused by TMZ. APNG expression is regulated through promoter methylation, and in patients with an unmethylated MGMT promoter receiving TMZ, the subset of APNG-negative tumors was reported to have a better prognosis. Peroxiredoxin 1 (PRDX1) is another interesting candidate, especially in the group of anaplastic astrocytomas. The PRDX1 promoter was found to be frequently hypermethylated in oligodendroglial tumors and secondary glioblastomas carrying a deletion of 1p/19q, leading to epigenetic downregulation of PRDX1 expression.19 In this study, silencing of PRDX1 in Hs683 glioma cells sensitized these cells both to TMZ and to RT in vitro. The objective of our present study was to determine the prevalence and impact of recently defined biomarkers associated with survival, heretofore established in younger patients, in an elderly collective. We hypothesized that these biomarkers might help to explain the heterogeneity in survival seen in the NOA-08 population. However, as our study revealed that they are virtually absent in elderly patients, we assume that relevant molecular differences exist among malignant gliomas of different age groups, which warrant further studies.