Methylation and colorectal cancer

Statistics rate colorectal adenocarcinoma as the most common cause of cance r death on exclusion of smoking-related neoplasia. However, the reported ac cumulation of genetic lesions over the adenoma to adenocarcinoma sequence c annot wholly account for the neoplastic phenotype. Recently, heritable, epi genetic changes in DNA methylation, in association with a repressive chroma tin structure, have been identified as critical determinants of tumour prog ression. Indeed, the transcriptional silencing of both established and nove l tumour suppressor genes has been attributed to the aberrant cytosine meth ylation of promoter-region CpG islands. This review aims to set these epige netic changes within the context of the colorectal adenoma to adenocarcinom a sequence. The role of cytosine methylation in physiological and pathologi cal gene silencing is discussed and the events behind aberrant cytosine met hylation in ageing and cancer are appraised. Emphasis is placed on the inte rrelationships between epigenetic and genetic lesions and the manner in whi ch they cooperate to define a CpG island methylator phenotype at an early s tage in tumourigenesis. Finally, the applications of epigenetics to molecul ar pathology and patient diagnosis and treatment are reviewed. Copyright (C ) 2001 John Wiley & Sons, Ltd.