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.

Microarray gene expression profiling in meningiomas: Differential expression according to grade or histopathological subtype

“…In these neoplasms, immunohistochemical analysis showed that loss of TIMP3 expression is especially frequent in tumours with poor differentiation (38). In meningiomas, no hypermethylation of the TIMP3 promoter has been detected (39) and no aberrant gene methylation of this gene has been reported (40). The silencing of the TIMP3 gene or its deletion, as it is located in a genomic region, 22q12, that is frequently deleted in meningioma (41), might be involved in the progression of this neoplasm.…”

Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors

“…Aberrant methylation of the promoter represents an alternative epigenetic change to the genetic mechanisms, leading to tumor suppressor gene inactivation. Methylation of specific subsets of CpG islands has been proposed to be associated with specific tumor types (Esteller et al, 2001;Bello et al, 2004). Hypermethylation of promoters usually occurs at CpG islands.…”

Methylation of O6-Methyl Guanine Methyltransferase Gene Promoter in Meningiomas - Comparison between Tumor Grades I, II, and III

“…There is a paucity of data in the existing literature on the status of MGMT methylation of meningiomas. Bello et al (Bello et al, 2004) detected aberrant MGMT methylation in 13%,26%, and 0% of grade I,II and III tumors. In another study Yanli liu et al (2005) reported the status of aberrant MGMT methylation in 6% ( 1/16) of grade I,5% (1/19) of grade II, and 8%(1/13) of grade III tumors.…”

“…The modified DNA was amplified using primers specific for either methylated or unmethylated MGMT promoter sequences. The primers were used in earlier reports (Bello et al, 2004) and are listed in Table 1.…”