Beyond the genetic lesions: Gene inactivation by promoter hypermethylation in human cancer

Genetic alterations in key genes are distinctive of a cancer cell. But the tumors also undergo other changes specific of the malignant transformation that do not affect the sequence of DNA. These are given the term epigenetic lesions, and the main one is aberrant methylation. In this review we focus in how promoter hypermethylation silences the expression of genes contributing to the neoplastic phenotype. Well recognized tumor suppressor genes such as p16/INK4a, BRCA1, Rb and V H L became hypermethylated in sporadic tumors with very selective patterns. Other genes recently characterized such as p14/ARF, LKB1, p73, E-cadherin and DAP-Kinase are also epigenetically inactivated in tumors. Furthermore, the methylation mediated silencing of DNA repair and detoxifier genes, such as the mismatch repair gene h MLH1, the alkylrepair MGMT and the carcinogen-protector GSTP1, may cause important genomic damage and mutations. All this recent data may provide a new avenue in how we understand the development, diagnosis and treatment of cancer.