The role of DNA methylation in colorectal carcinogenesis and prognosis
Colorectal cancer is one of the commonest cancers world-wide. Surgery remains the mainstay of treatment however an increasing emphasis is now placed on adjuvant treatment with chemotherapy and radiotherapy incorporating a multi-disciplinary approach to cancer care. Clinical background and pathological staging systems remain the most important predictive and prognostic indicators.
It is well-established that colorectal cancers develop via the adenoma-carcinoma sequence. This sequence is characterised by a step-wise accumulation of genetic mutational changes involving primarily the adenomatous polyposis coli (APC). K-Ras and p53 genes. In addition, the microsatellite instability pathway is responsible for almost all of the hereditary colorectal cancers. Despite ongoing research into these known genetic markers involved in colorectal carcinogenesis, clinical application in diagnosis and prognosis is still limited.
Recently, a novel molecular pathway involving epigenetic mechanisms has been described. This is now recognised to be an additional and distinctive molecular pathway to most neoplasia including colorectal cancers. This pathway is characterised by gene-silencing, most commonly through the process of DNA methylation of promoter regions of genes involved in carcinogenesis.
The aim of this thesis was to examine the role DNA methylation plays in colorectal carcinogenesis, in particular its potential as a prognostic marker in colorectal cancer as well as a predictor of response to neoadjuvaut chemoradiotherapy in rectal cancer.
Materials and Methods:
Patients with colorectal cancer were identified and samples retrieved from the pathology tissue bank. Immunohistochemical staining was performed using the conmercially available 5-Methylcytidine (Euuogentec®, Belgium) and Ki-67 (DakoCytomation®, Denmark) antibodies. Automated image analysis of staining was carried out using the Aperio® (Vista, CA) image analysis platform. Image analysis results were correlated with clinico-pathological data of individual patients including response to neoadjuvant treatment and survival. Ethical approval was obtained from the local hospitals' ethics committees (Appendix V). Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS®) version 17.