title: Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective.
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.
authors.affiliation: German Cancer Consortium, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Hartlieb
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Schliesser
authors.forename: Elisa K
authors.initials: EK
authors.lastname: Weiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dittmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Meisner
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Caroline
authors.initials: C
authors.lastname: Happold
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Guido
authors.initials: G
authors.lastname: Nikkhah
authors.forename: Kirsten
authors.initials: K
authors.lastname: Papsdorf
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Michael
authors.initials: M
authors.lastname: Sabel
authors.forename: Christiane
authors.initials: C
authors.lastname: Grimm
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Björn
authors.initials: B
authors.lastname: Tews
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Wolf
authors.initials: W
authors.lastname: Müller
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D006657:Histones / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: APNG methylation; G-CIMP; H3F3A mutation; IDH mutation; PRDX1 methylation; glioblastoma