TFAP2E Methylation and Expression Status Does Not Predict Response to 5FU-based Chemotherapy in Colorectal Cancer

Purpose:A recent study reported that 5-fluorouracil (5FU)-based chemotherapy is less effective in treating advanced colorectal cancer (CRC) patients demonstrating hypermethylation of TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 CRC patients: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of CRC patients to 5FU-based chemotherapy. DNA methylation status of the TFAP2E gene in CRC patients was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 CRC. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients (HR 1.21; 95% CI 0.79-1.87; log rank p 0.6). In stage II-III cases disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU treated (HR 0.91; 95% CI 0.52-1.59; log rank p 0.9) as well as in non-treated patients (HR 0.88; 95% CI 0.5-1.54; log rank p 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5FU-based chemotherapy in CRC patients.

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