In NEJM this week, researchers in Germany and Ireland report on a study on the links between chemoresistance in advanced colorectal cancer and function of the genes TFAP2E and DKK4. Alterations in TFAP2E are common in several human cancers, and DKK4 — a potential downstream target of TFAP2E — has been implicated in resistance to chemotherapy, the team says. For this study, the researchers analyzed the expression and function of TFAP2E in colorectal cancer cell lines and in patients with the disease. They found that TFAP2E was hypermethylated in 51 percent of the patients in the initial cohort, which was associated with decreased expression of the gene in primary and metastatic colorectal cancer cell lines and tissue samples. In addition, cell lines that over-expressed DKK4 were increasingly resistant to the chemotherapy fluorouracil, though not irinotecan or oxaliplatin. "TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer," the authors write. "Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance."
In a letter to NEJM this week, three French researchers write that they have found acquired TET2 mutations in human myeloid cancers and T-cell lymphomas, which may help explain the genetic basis of these conditions. The researchers investigated the DNMT3A gene, which is also mutated in human myeloid cancers, and found that a majority of patients they studied who had DNMT3A mutations also had TET2 mutations. "The association between the two mutations was significant," the authors write. "Our data extend the common mutations linking T-cell lymphoma and myeloid cancer and provide a further basis for the molecular classification of T-cell lymphomas. They also suggest an oncogenic cooperation between TET2 and DNMT3A mutations that may involve deregulation of the cytosine methylation and demethylation processes."