Epigenetic Alterations and Loss of Imprinting in Colorectal Cancer

Kim, Jong Woo

Abstract

Two forms of genomic instability have been described in colorectal cancer: chromosomal (CIN) and microsatellite instability (MIN). Colorectal cancer has been considered to progress through one of these two major pathways. However, recently a CpG island methylator pathway (CIMP) has been established among sporadic MIN cancers. Aberrant methylation of a promoter CpG island is associated with inactivation of tumor suppressor genes and is one of the epigenetic alterations identified to be involved in tumorigenesis. Now, several types of epigenetic alterations appear to play roles complementary to genetic mutations in colorectal carcinogenesis and seem to contribute to the progression of cancer. Epigenetic alterations also increase the probability that genetic changes will lead to cancer initiation. So far, major epigenetic alterations have been categorized into four groups of dysregulations: 1) hypomethylation with oncogene activation and chromosomal instability, 2) hypermethylation with tumor suppressor gene silencing, 3) chromatin modifications, and 4) loss of imprinting (LOI). Especially, LOI is a common epigenetic variant and should have a field effect on the colon, making it more vulnerable to genetic insults. Genomic imprinting is parental-origin-specific allele silencing, a form of gene silencing that is epigenetic in origin and does not involving alterations in the DNA sequence but does involve methylation and other modifications that are heritable during cell division. LOI is the loss of parental-origin-specific marks, leading either to aberrant activation of a normally silent allele of a growth promoter gene or to silencing of the growth inhibitor allele. Most of the attention has been focused on LOI of the IGF2 (insulin-like growth factor II) gene in a Wilms' tumor and colorectal cancer. LOI of IGF2 involves abnormal activation of a normally silent maternally inherited allele and has been associated with personal and family history of colorectal cancer, supporting a role for LOI in carcinogenesis. LOI may be a valuable predictive marker of an individual's risk for colorectal cancer. Now, epigenetics and imprinting are emerging areas in the study of human-cancer genetics.