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Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery in rectal cancer has several adverse effects. Predictive biomarkers for response to nCRT are needed to save patients unnecessary toxicities and to take a timely tailored treatment decision. Epigenetic modifications like DNA methylation patterns have been suspected to be potential predictive biomarkers. Aim: To determine the role of TFAP2E and MLH1 genes’ methylation status and microsatellite instability (MSI) in predicting response to 5-fluorouracil – based nCRT in rectal cancer. Methods: DNA was extracted from 80 patients with newly diagnosed stage II / III rectal cancer. The methylation status of TFAP2E and MLH1 genes was determined by pyrosequencing and MSI was determined using 5 microsatellite loci by conventional polymerase chain reaction and capillary electrophoresis. Results: The cut-off values for TFAP2E & MLH1 genes ’methylation level were 40% and 15% by receiver operating characteristic curve analysis. Hypermethylated TFAP2E and MLH1 gene promotors and MSI were predominant among non-responders (p <0.001, <0.001 and =0.022; respectively). Other factors associated with significantly higher pathological response to nCRT were well/moderately differentiated adenocarcinoma, pretreatment carcinoembryonic antigen level ≤5 ng/ml and rectal tumor ≤5 cm from the anal verge. Conclusion: Hypermethylated TFAP2E and MLH1 gene promotors and MSI in rectal cancer tissue were associated with poor response to 5-fluorouracil – based nCRT. They might be of value in predicting the response of rectal cancer to nCRT and in tailoring its treatment.

TFAP2E and MLH1 Genes Methylation Pattern and Microsatellite Instability as Predictors of Rectal Cancer Response to Neoadjuvant Chemoradiotherapy