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


Wiestler, B; Claus, R; Hartlieb, S A; Schliesser, M G; Weiss, E K; Hielscher, T; Platten, M; Dittmann, L M; Meisner, C; Felsberg, J; Happold, C; Simon, M; Nikkhah, G; Papsdorf, K; Steinbach, J P; Sabel, M; Grimm, C; Weichenhan, D; Tews, B; Reifenberger, G; Capper, D; Müller, W; Plass, C; Weller, M; Wick, W (2013). Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective. Neuro-Oncology, 15(8):1017-1026.

Abstract

Background The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients. Methods Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial. Results IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival. Conclusions Despite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.

Abstract

Background The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients. Methods Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial. Results IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival. Conclusions Despite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:28 Nov 2013 07:11
Last Modified:05 Aug 2017 13:36
Publisher:Oxford University Press
ISSN:1522-8517
Additional Information:This is a pre-copyedited, author-produced PDF of an article accepted for publication in Neuro-Oncology following peer review. The definitive publisher-authenticated version Wiestler, B; Claus, R; Hartlieb, S A; Schliesser, M G; Weiss, E K; Hielscher, T; Platten, M; Dittmann, L M; Meisner, C; Felsberg, J; Happold, C; Simon, M; Nikkhah, G; Papsdorf, K; Steinbach, J P; Sabel, M; Grimm, C; Weichenhan, D; Tews, B; Reifenberger, G; Capper, D; Müller, W; Plass, C; Weller, M; Wick, W (2013). Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective. Neuro-Oncology, 15(8):1017-1026. is available online at: http://neuro-oncology.oxfordjournals.org/content/15/8/1017.long
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/neuonc/not043
PubMed ID:23595628

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