<i>TFAP2E</i> Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer.

Abstract

<b>Purpose:</b> A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the <i>TFAP2E</i> gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts.<b>Experimental Design:</b> Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of <i>TFAP2E</i> methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the <i>TFAP2E</i> gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.<b>Results:</b> Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by <i>TFAP2E</i> hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank <i>P</i> = 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 <i>P</i> = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank <i>P</i> = 0.7).<b>Conclusions:</b><i>TFAP2E</i> hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that <i>TFAP2E</i> methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. <i>Clin Cancer Res; 24(12); 2820-7. ©2018 AACR</i>.