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[Cancer Research 61, 4689-4692, June 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Promoter Hypermethylation of the DNA Repair Gene O6-Methylguanine-DNA Methyltransferase Is Associated with the Presence of G:C to A:T Transition Mutations in p53 in Human Colorectal Tumorigenesis1

Manel Esteller, Rosa-Ana Risques, Minoru Toyota, Gabriel Capella, Victor Moreno, Miquel Angel Peinado, Stephen B. Baylin and James G. Herman2

Tumor Biology, The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., S. B. B., J. G. H.]; Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, Majadahonda 28220, Spain [M. E.]; First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan [M. T.]; Institut Catala d’Oncologia and Institut de Recerca Oncologica, Hospital Duran i Reynals, Barcelona, Catalonia 08907, Spain [R-A. R., G. C., V. M., M. A. P.]

Defects in DNA repair may be responsible for the genesis of mutations in key genes in cancer cells. The tumor suppressor gene p53 is commonly mutated in human cancer by missense point mutations, most of them G:C to A:T transitions. A recognized cause for this type of change is spontaneous deamination of the methylcytosine. However, the persistence of a premutagenic O6-methylguanine can also be invoked. This last lesion is removed in the normal cell by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In many tumor types, epigenetic silencing of MGMT by promoter hypermethylation has been demonstrated and linked to the appearance of G to A mutations in the K-ras oncogene in colorectal tumors. To study the relevance of defective MGMT function by aberrant methylation in relation to the presence of p53 mutations, we studied 314 colorectal tumors for MGMT promoter hypermethylation and p53 mutational spectrum. Inactivation of MGMT by aberrant methylation was associated with the appearance of G:C to A:T transition mutations at p53 (Fischer’s exact test, two-tailed; P = 0.01). Overall, MGMT methylated tumors displayed p53 transition mutations in 43 of 126 (34%) cases, whereas MGMT unmethylated tumors only showed G:C to A:T changes in 37 of 188 (19%) tumors. A more striking association was found in G:C to A:T transitions in non-CpG dinucleotides; 71% (12 of 17) of the total non-CpG transition mutations in p53 were observed in MGMT aberrantly methylated tumors (Fischer’s exact test, two-tailed; P = 0.008). Our data suggest that epigenetic silencing of MGMT by promoter hypermethylation may lead to G:C to A:T transition mutations in p53.




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