MGMT hypermethylation: a prognostic foe, a predictive friend.
Alkylation of DNA at the O(6)-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. O(6)-alkylguanine-DNA alkyltransferase (AGT), also known as O(6)-methylguanine-DNA methyltransferase (MGMT), is the DNA repair protein responsible for removing alkylation adducts from the O(6)-position of guanine in DNA. The promoter CpG island hypermethylation-associated gene silencing of MGMT is associated with a wide spectrum of human tumors. This epigenetic inactivation of MGMT has two main consequences in human cancer. First, it uncovers a new mutator pathway that causes the accumulation of G-to-A transition mutations that can affect genes required for genomic stability. Second, there is a strong and significant positive correlation between MGMT promoter hypermethylation and increased tumor sensitivity to alkylating drugs. These findings underline the importance of MGMT promoter hypermethylation in basic and translational cancer research.
Jacinto
Filipe V
FV
Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Esteller
Manel
M
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004260:DNA Repair; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic
D000477:Alkylating Agents; D019853:O(6)-Methylguanine-DNA Methyltransferase