Colorectal Cancer Epigenetics: Complex Simplicity

Colorectal cancer (CRC) has predominantly been considered a genetic disease, characterized by sequential accumulation of genetic alterations. Growing evidence indicates that epigenetic alterations add an additional layer of complexity to the pathogenesis of CRC, and characterize a subgroup of colorectal cancers with a distinct etiology and prognosis. Epigenetic dysregulation in colorectal cancer is organized at multiple levels, involving DNA methylation, histone modifications, nucleosomal occupancy and remodeling, chromatin looping, and noncoding RNAs. Interactions between these processes and complex associations with genetic alterations have recently been unraveled. It appears that CRC epigenetics will be the paradigm for multistep carcinogenesis, as CRC genetics has been for the past three decades. This review integrates recent data on epigenetic regulation of gene expression in CRC and describes how the understanding of these processes will alter the management of CRC. J Clin Oncol 29: 1382-1391.