(HealthDay News) – In colorectal cancer patients, hypermethylation of the gene encoding transcription factor AP-2 epsilon (TFAP2E), which targets a gene involved in chemoresistance (dickkopf homolog 4 protein [DKK4]), is associated with treatment resistance to fluorouracil but not irinotecan or oxaliplatin, according to a study published in the January 5 issue of the New England Journal of Medicine.
Matthias P.A. Ebert, MD, of the University of Mannheim in Germany, and colleagues attempted to evaluate the role of TFAP2E and DKK4 as potential predictors of response to chemotherapy for colorectal cancer. To do this, the investigators analyzed the expression, methylation, and function of TFAP2E in colorectal cancer cell lines obtained from 74 patients as well as a further 220 patients who received chemotherapy or chemoradiation.
The researchers found that, in the initial cohort of patients, more than half (51 percent) exhibited hypermethylated TFAP2E, which was associated with reduced expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. In the remaining patient cohorts, those without hypermethylation of TFAP2E were about six times more likely to respond to chemotherapy, and those with hypermethylation of TFAP2E were significantly less likely to respond to chemotherapy.
“Overall, our data indicate that fluorouracil-based chemotherapy is largely ineffective in patients with colorectal cancer with TFAP2E hypermethylation. Specific targeting of DKK4 in these individuals may therefore be an option for overcoming TFAP2E-mediated chemoresistance,” the authors write.