title: Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q.
abstract: Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio- and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2'-deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.
authors.affiliation: Division of Molecular Genetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Tews
authors.forename: P
authors.initials: P
authors.lastname: Roerig
authors.forename: C
authors.initials: C
authors.lastname: Hartmann
authors.forename: M
authors.initials: M
authors.lastname: Hahn
authors.forename: J
authors.initials: J
authors.lastname: Felsberg
authors.forename: B
authors.initials: B
authors.lastname: Blaschke
authors.forename: M
authors.initials: M
authors.lastname: Sabel
authors.forename: A
authors.initials: A
authors.lastname: Kunitz
authors.forename: G
authors.initials: G
authors.lastname: Toedt
authors.forename: K
authors.initials: K
authors.lastname: Neben
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
authors.forename: P
authors.initials: P
authors.lastname: Lichter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality; D002648:Child; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009837:Oligodendroglioma / Q000235:genetics* / Q000401:mortality; D011110:Polymorphism, Genetic; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C451405:CITED4 protein, human; D014157:Transcription Factors