Hypermethylation of TFAP2E Gene in Colorectal Cancer Associated With Unresponsiveness to the Chemotherapy Fluorouracil

In conjunction with the identification of the mechanism of resistance of BRAF-mutated colorectal tumors to BRAF inhibitors, a study published in the New England Journal of Medicine (N Engl J Med 2012;366:44-53) identifies specific colorectal tumors that are less responsive to chemotherapy.

Chemical structure and 3D representation of Fluorouracil

Matthias P.A. Ebert, MD, assistant professor of internal medicine at the University of Magdeburg, and colleagues show that the hypermethylation of the transcription factor AP-2 epsilon (TFAP2E) gene results in lower expression of the TFAP2E protein and upregulation of the DKK4 gene.

DKK4 has been previously associated with resistance to the chemotherapy fluorouracil.

Patients with hypomethylation of the TFAP2E gene were about 6 times more likely to respond to the chemotherapy compared to the entire patient population. These aberrations in the TFAP2E gene were independent of mutations in colorectal driver mutations. Hypermethylation of the gene was significantly associated with unresponsiveness to chemotherapy (P < .001).

While chemotherapy has shown improved survival for colorectal patients, this is one of the first potential predictors of response to systemic therapy. Dr. Ebert warns that this data is still preliminary and needs to be validated in a prospective trial.

"We performed a retrospective study. Before these findings can be used in the clinical management of cancer patients, a prospective validation is required. At this time, analysis of TFAP2E should not be used for clinical decision making," Ebert emphasized.

Ebert and colleagues are undertaking a trial to follow up on their current data. "We are planning to conduct a prospective translational study to validate the role of TFAP2E, furthermore we are looking into the functional role of DKK4 and TFAP in chemoresistance," Ebert explained.

"We do not know very much about [the TFAP2E and DKK4 genes] and their role in colorectal cancer development, this is a focus of our current research," Dr. Ebert elaborated.