title: DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q.
abstract: The purpose of this research was to examine the DNA methylation profile of meningiomas. Accordingly, we examined the DNA methylation status of ten tumor-related genes (RB1, p16(INK4a), p73, MGMT, ER, DAPK, TIMP-3, p14(ARF), THBS1, and Caspase-8) in 98 meningiomas (68 grade I; 27 grade II; and 3 grade III samples) using methylation-specific PCR and sequencing. The most frequently methylated genes were THBS1 (30%), TIMP-3 (24%), p16(INK4a) (17%), MGMT (16%), p73 (15%), ER (15%), and p14(ARF) (13%), whereas methylation was relatively rare in the other genes (<10%). Methylation occurred in at least one gene in 77.5% of the cases and in three or more genes in 25.5%. Methylation was tumor specific since it was absent in the controls: two non-neoplastic meningeal samples and two non-neoplastic brain samples. The frequency of aberrant gene methylation in grade I versus grade II-III tumors showed some differences for TIMP-3, THBS1, MGMT, p16(INK4a) and p73; these differences reached statistical significance for TIMP-3: 18% in grade I versus 40% in grade II-III (P < 0.02). Our previous loss of heterozygosity studies provided the allelic constitution at 1p and 22q for 60 of the 98 meningiomas included in this report. The level of aberrant promoter methylation increased in tumors (30 samples) displaying 1p loss (either isolated or as concurrent deletion at 1p/22q; P = 0.014). These meningiomas primarily accumulated the epigenetic changes of THBS1 (14/30; 47%; P < 0.005), TIMP-3 (12/30; 40%; P < 0.05), p73 (10/30; 26%; P < 0.02) and p14(ARF) /p16(INK4a)(7/30 each one; 23%; not significant). Our findings indicate that aberrant DNA methylation of promoter-associated CpG islands in meningiomas contributes to the development of these tumors.
authors.affiliation: Department of C. Experimental, Laboratorio Oncogenetica Molecular, Hospital Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Spain.
authors.forename: M Josefa
authors.initials: MJ
authors.lastname: Bello
authors.forename: Cinthia
authors.initials: C
authors.lastname: Amiñoso
authors.forename: Isabel
authors.initials: I
authors.lastname: Lopez-Marin
authors.forename: Dolores
authors.initials: D
authors.lastname: Arjona
authors.forename: Pilar
authors.initials: P
authors.lastname: Gonzalez-Gomez
authors.forename: M Eva
authors.initials: ME
authors.lastname: Alonso
authors.forename: Jesus
authors.initials: J
authors.lastname: Lomas
authors.forename: Jose M
authors.initials: JM
authors.lastname: de Campos
authors.forename: M Elena
authors.initials: ME
authors.lastname: Kusak
authors.forename: Jesus
authors.initials: J
authors.lastname: Vaquero
authors.forename: Alberto
authors.initials: A
authors.lastname: Isla
authors.forename: Manuel
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sarasa
authors.forename: Juan A
authors.initials: JA
authors.lastname: Rey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
chemical_list: D004273:DNA, Neoplasm