Journal Article

Promoter methylation of the DNA repair gene <i>MGMT</i> in astrocytomas is frequently associated with G:C → A:T mutations of the <i>TP53</i> tumor suppressor gene

Mitsutoshi Nakamura, Takao Watanabe, Yasuhiro Yonekawa, Paul Kleihues and Hiroko Ohgaki

in Carcinogenesis

Volume 22, issue 10, pages 1715-1719
Published in print October 2001 | ISSN: 0143-3334
Published online October 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.10.1715
Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C → A:T mutations of the TP53 tumor suppressor gene

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O6-Methylguanine-DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from the O6 position of guanine in DNA. Repair of O6-alkylguanine adducts by tumour cells has been implicated in drug resistance since it reduces the cytotoxicity of alkylating chemotherapeutic agents. We assessed promoter methylation of the MGMT gene in astrocytic brain tumours by methylation-specific PCR. MGMT promoter methylation was detected in 26 of 54 (48%) low-grade diffuse astrocytomas (WHO grade II) and in 12 of 16 (75%) of secondary glioblastomas (WHO grade IV) that had progressed from low-grade astrocytomas. The frequency of MGMT methylation was significantly lower in primary (de novo) glioblastomas (13 of 36, 36%, P = 0.0155). The majority of low-grade astrocytomas with MGMT methylation (24/26, 92%) contained a TP53 mutation, whereas only 11 out of 28 (39%) cases without MGMT methylation carried a TP53 mutation (P < 0.0001). Furthermore, G:C → A:T transition mutations at CpG sites were significantly more frequent in low-grade astrocytomas with MGMT methylation (15/26, 58%) than in those without (3/28, 11%, P = 0.0004). These results suggest that loss of MGMT expression as a result of promoter methylation, which frequently occurs at an early stage in the pathway leading to secondary glioblastomas, appears to be associated with increased frequency of TP53 mutations, in particular G:C → A:T transitions.

Keywords: BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; MGMT, O6-Methylguanine-DNA methyltransferase.

Journal Article.  4085 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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