Epigenetic Drivers of Genetic Alterations in Cancer

Abstract

Abstract In cancer cells, aberrant deoxyribonucleic acid (DNA) methylation plays key roles in the epigenetic dysregulation of tumour‐related genes, thereby affecting numerous cellular processes. Here we discuss the mechanism by which epigenetic events drive genetic alterations in cancer. Epigenetic inactivation of mutL homolog 1 ( MLH1 ) is a major cause of microsatellite instability, while methylation of O ‐6‐methylguanine‐DNA methyltransferase ( MGMT ) is often associated with specific mutations. In addition, the silencing of breast cancer 1 ( BRCA1 ), Fanconi anemia, complementation group F ( FANCF ) and checkpoint with forkhead and ring finger domains ( CHFR ) impairs the machinery involved in maintaining genomic integrity. Conversely, a recently discovered link between isocitrate dehydrogenase 1 ( IDH1 )/ 2 or tet methylcytosine dioxygenase 2 ( TET2 ) mutations and genome‐wide aberrant methylation suggests the hypermethylator phenotype may lie downstream of genetic alterations. Dissecting the association between epigenetic and genetic alterations could provide important clues for developing novel approaches to the treatment of cancer. Key Concepts: Epigenetic alteration of driver genes can lead to genetic alterations in cancer. Epigenetic drivers include genes involved in DNA repair and cell cycle checkpoints. Global hypomethylation may be another epigenetic driver that induces chromosomal instability. Epigenetic alteration of driver genes is often associated with the CpG island methylator phenotype (CIMP). The CIMP may lie downstream of specific gene mutations.