Abstract
There is much debate around the preoperative treatment of colorectal cancer and, in particular, neoadjuvant chemoradiotherapy in locally advanced rectal cancer. This treatment carries a significant risk of harmful side effects and has a highly variable response rate. Predictive biomarkers have been the subject of a great deal of study with the aim of pretreatment risk stratification in order to more accurately determine which patients will derive the most benefit and least harm from these treatments. The study of epigenetics in colorectal cancer is relatively recent, and distinct patterns of aberrant DNA methylation, in particular the cytosine-phosphate-guanine (CpG) island methylator phenotype (CIMP), have been demonstrated in colorectal cancer, and their characterisation and significance are under debate, particularly in rectal cancer. These patterns of DNA methylation have been associated with differences in response to therapy and treatment outcomes and therefore have the potential to be used as biomarkers in tailored therapy regimes for patients with rectal cancer. This review aims to summarise the current state of the art in rectal cancer, with particular regard to the determination of DNA methylation patterns, the CpG island methylator phenotype and its potential as a novel biomarker in rectal cancer treatment and prediction of outcomes and response after neoadjuvant chemoradiotherapy.
Highlights
Neoadjuvant chemoradiotherapy is currently recommended by the National Institute for Health and Clinical Excellence (NICE) [1] prior to surgical resection for patients with advanced stage (T3–4) rectal tumours and those with nodal disease in order to reduce rates of locoregional recurrence and potential circumferential margin involvement.It is increasingly recognised that this preoperative chemoradiotherapy is associated with significant adverse effects including faecal and urinary incontinence, delayed wound healing and sexual dysfunction [2]
There have been similar efforts in the study of DNA methylation in rectal cancers, and this review aims to summarise the current state of the art in this group of patients
Gaedcke et al [57] applied a whole-genome methylation analysis to identify several differentially methylated regions (DMR), in which high-pretreatment levels of methylation imparted a better prognosis in terms of disease-free survival in 165 patients in three cohorts treated for locally advanced rectal cancer
Summary
Gaedcke et al [57] applied a whole-genome methylation analysis to identify several differentially methylated regions (DMR), in which high-pretreatment levels of methylation imparted a better prognosis in terms of disease-free survival in 165 patients in three cohorts treated for locally advanced rectal cancer (hazard ratios between 3.57 and 4.09, P < 0.05) These cohorts included a tight group of selected patients undergoing standardised 5-FU-based chemoradiotherapy as well as a more heterogenous group undergoing radiotherapy as monotherapy or in combination at various doses with various agents including oxaliplatin. These MINT loci are non-protein-encoding CpG-rich regions which have been previously identified as hypermethylated in colorectal cancer and form part of many CIMP marker panels This group identified a cohort of rectal cancer patients undergoing surgery without neoadjuvant treatment in whom hypermethylation at MINT3 and hypomethylation at MINT17 loci were associated with a significantly reduced risk of local recurrence compared with others not demonstrating these epigenetic features. Hypermethylation associated with deficient CRC cell lines increased response to IR
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