Identifying DNA methylation biomarkers of cancer drug response.

In the last few years, DNA methylation has become one of the most studied gene regulation mechanisms in carcinogenesis as a result of the cumulative evidence produced by the scientific community. Moreover, advances in the technologies that allow detection of DNA methylation in a variety of analytes have opened the possibility of developing methylation-based tests. A number of studies have provided evidence that specific methylation changes can alter the response to different therapeutic agents in cancer and, therefore, be useful biomarkers. For example, the association of the methylation status of DNA repair genes such as MGMT and MLH1 illustrate the two main mechanisms of response to DNA damaging agents. Loss of methylation of MGMT, and the subsequent increase in gene expression, leads to a reduction in response to alkylating agents as a result of enhanced repair of drug-induced DNA damage. Conversely, the increase in methylation of MLH1 and its resulting loss of expression has been consistently observed in drug-resistant tumor cells. MLH1 encodes a mismatch repair enzyme activated in response to DNA damage; activation of MLH1 also induces apoptosis of tumor cells, and thus loss of its expression leads to resistance to DNA-damaging agents. Other methylation-regulated genes that could serve as biomarkers in cancer therapy include drug transporters, genes involved in microtubule formation and stability, and genes related to hormonal therapy response. These methylation markers have potential applications for disease prognosis, treatment response prediction, and the development of novel treatment strategies.

DNA methylation markers - an opportunity to further individualize therapy in breast cancer?

Over the last few decades, a wealth of treatment options have become available for breast cancer. To specifically direct those therapies to patients with the highest need who will receive the greatest benefit, biomarkers are urgently needed. Two specific needs seem to be most pressing: first is the need for prognostic markers, which would determine which group of patients may recover without adjuvant chemotherapy. Second, predictive markers for specific treatments, such as different endocrine treatments, chemotherapies or targeted drugs, are expected to play a major role in the near future. Ideally, such markers should be strong single markers, or low-complexity marker panels containing only a few markers, to allow for easier assay development and improved reproducibility. The possibility to measure the marker(s) in formalin-fixed specimens would greatly facilitate integration into routine clinical practice. A common and early event in breast cancer is aberrant DNA methylation within gene regulatory regions, affecting a variety of genes with different functions. Data from recently published studies indicate that altered DNA methylation carries prognostic as well as predictive information in breast cancer. Together with the technical advantages of a DNA-based marker, DNA methylation may well constitute the ideal biomarker to further individualize breast cancer treatment. Here the recent literature is reviewed and the most interesting markers, which have the potential to significantly change breast cancer treatment and, therefore, warrant further systematic clinical validation, are highlighted.