title: Aberrant promoter hypermethylation profile of cell cycle regulatory genes in malignant astrocytomas.
abstract: Aberrant hypermethylation of the CpG islands in the promoter region plays a casual role in the inactivation of various key genes involved in the cell cycle regulatory cascade, which could result in loss of cell cycle control. The aim of the present study was to investigate the role of promoter methylation of genes with a proven involvement in the cell cycle regulation of malignant astrocytomas. We profiled the CpG island methylation status of the RB1, p14ARF, p15INK4b, p16INK4a, p21Waf1/Cip1, p27Kip1, and p73 genes by methylation-specific polymerase chain reaction assay in a homogeneous cohort of patients with malignant astrocytomas, and assessed their relationships with clinical behavior. Promoter hypermethylation of the RB1, p14ARF, p15INK4b, p16INK4a, p21Waf1/Cip1, p27Kip1, and p73 genes was detected in 3 (6%), 7 (13%), 4 (7%), 2 (4%), 1 (2%), 3 (6%), and 12 samples (22%) among 54 newly diagnosed malignant astrocytomas, respectively. A total of 50% of the cases carried methylation of at least one gene, and only 9% of the cases displayed concordant hypermethylation of two genes. None of the tumors disclosed three or more methylated loci. The presence of methylation of these genes or a group of genes was not associated with any distinct clinicopathological characteristics including tumor grade, proliferation activity, responsiveness to adjuvant therapy, or patient survival. p73 protein accumulation was demonstrated by immunohistochemical staining in 6 (15%) of the 40 samples examined, with no significant association with the methylation status of p73 and any of the clinicopathological parameters tested. Our results demonstrated that a significant fraction of malignant astrocytomas displayed at least one methylated locus of the key cell cycle-related genes, although the genes were rarely hypermethylated, independent of the clinicopathological parameters. Thus, this epigenetic change is unlikely to play an important role in the evolution and development of malignant astrocytomas.
authors.affiliation: Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohta
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Katayama
authors.forename: Atsuo
authors.initials: A
authors.lastname: Yoshino
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yachi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ogino
authors.forename: Chiaki
authors.initials: C
authors.lastname: Komine
authors.forename: Takao
authors.initials: T
authors.lastname: Fukushima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D016160:Retinoblastoma Protein / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins