HOW WILL INCREASED UNDERSTANDING OF EPIGENETICS IMPACT HEALTH CARE?
Epigenetics is expected to have an increasingly important role in disease diagnosis and treatment, especially in cancer. Identifying methylation or its readout (i.e., altered gene expression) at cancer-causing genes such as BRCA1 will likely be a useful diagnostic and possibly prognostic marker (Figure 1). Indeed, BRCA1 methylation is associated with shorter survival than BRCA1 mutation. Similarly, detecting changes in chromatin modifications is expected to have utility.
Figure 1. DNA methylation and BRCA. The distribution of ovarian cancer genomes with alterations in their BRCA1 and BRCA2 genes based on mutations and DNA methylation. Although the sample size was small (103), the analysis clearly revealed that BRCA1 can be inactivated by either mutation or DNA methylation. BRCA1 methylation is associated with shorter survival than BRCA1 mutation.
In addition, there are instances in which DNA methylation status may be used to infer drug sensitivity and guide treatment. For example, DNA methylation status has value in predicting response to alkylating chemotherapy (temozolomide) in glioma. Alkylating chemotherapy works by damaging DNA and killing tumor cells. The level of expression of the DNA repair enzyme, MGMT, influences the effectiveness of alkylating chemotherapy—low levels of MGMT correlate with increased chemosensitivity. Methylation of the promoter of the MGMT gene (which represses gene expression) is correlated with better responses to temozolomide in glioma.
Eventually, it is likely that screening for disease risk in healthy people will include analyses of both the genome and the epigenome. (See Figure 2) for an example from the author’s genome.) Genes suspected to be aberrantly expressed—either due to DNA methylation, mutation, or both—will be identified. Findings will be confirmed by gene expression analyses. Thus, in the future we can expect that genomic and epigenomic analyses will both be utilized for predicting disease risk and integrated into health management strategies.
Figure 2. Analysis of the genome and epigenome reveals inactivation of PDE4 by a combination of deleterious mutation in one copy of the gene and methylation of promoter DNA in the other copy of the gene. Expression analysis showed that only the gene with the deleterious mutation was highly expressed, indicating that both copies of PDE4 are not functional.