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Published on: May 17, 2013
Epigenetics in colorectal cancer
Lanlan Shen1, Jean-Pierre J Issa
1The University of Texas at MD Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Malignant transformation is now known to require a series of molecular alterations that disrupt a limited number of pathways including autocrine and paracrine responses to growth factors, cell-cycle control, senescence, motility, and invasion. Studies on hereditary cancers have established genetic changes as the primary driving force for these molecular alterations. Recently, however, it has been recognized that epigenetic changes, defined as clonal changes in gene expression without accompanying changes in primary DNA coding sequence, can also be a driving force in neoplastic transformation, for selected genes, and in specific tumors. DNA methylation within gene promoters and associated alterations in histone acetylation appear primary mediators of epigenetic inheritance in cancer cells. In the large intestine, aberrant DNA methylation arises very early, initially in normal-appearing mucosa, and may be part of the age-related field defect observed in sporadic colorectal neoplasia. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed cytosine phosphoguanosine (CpG) island methylator phenotype (CIMP), which appears to be a defining event in approximately half of all sporadic tumors. In sporadic colon cancer, CIMP has distinct epidemiologic and clinical features and is responsible for most cases of microsatellite instability related to hMLH1 inactivation. The recognition of epigenetic changes as a driving force in colorectal neoplasia opens new areas of research in disease epidemiology, risk assessment, screening, and treatment.
Insights
Epigenetic changes, like DNA methylation, drive cancer development, particularly in the colon. These changes, especially the CpG island methylator phenotype (CIMP), are crucial in sporadic colorectal neoplasia.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Malignant transformation involves molecular alterations in growth factor response, cell-cycle control, and invasion.
- Genetic changes are traditionally seen as the primary drivers of hereditary cancers.
- Epigenetic changes, altering gene expression without DNA sequence modification, are increasingly recognized as drivers of neoplastic transformation.
Purpose of the Study:
- To highlight the role of epigenetic changes, specifically DNA methylation, in cancer development.
- To discuss the significance of the CpG island methylator phenotype (CIMP) in sporadic colorectal neoplasia.
- To explore the implications of epigenetic alterations for cancer research and clinical applications.
Main Methods:
- Review of molecular alterations in malignant transformation.
- Focus on DNA methylation and histone acetylation as epigenetic mediators.
- Analysis of aberrant methylation in early colorectal neoplasia and its association with CIMP.
Main Results:
- Epigenetic changes, particularly DNA methylation, are key drivers in neoplastic transformation.
- Aberrant DNA methylation occurs early in colorectal neoplasia, potentially contributing to a field defect.
- The CpG island methylator phenotype (CIMP) is a critical event in approximately half of sporadic colon tumors, influencing distinct clinical and epidemiological features and causing microsatellite instability via hMLH1 inactivation.
Conclusions:
- Epigenetic alterations are significant driving forces in colorectal neoplasia.
- CIMP is a defining characteristic of a subset of sporadic colon cancers with unique features.
- Understanding epigenetic changes opens new avenues for cancer epidemiology, risk assessment, screening, and treatment.
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