Figure 1. Genetic and epigenetic contributions to tumor heterogeneity.

During oncogenesis, environmental stress such as chronic inflammation, accumulating reactive oxygen species (ROS) or aging, may promote clonal expansion of cells with genetic or epigenetic abnormalities. These cells then acquire further mutations or epigenetic alterations and become founder tumor cells that initiate pre-cancer or cancer. The evolution of tumor clones continues as tumors develop. In an established tumor, the parental subclone may acquire new driver or passenger mutations (genetic subclone), or undergo epigenetic alterations on the levels of chromatin or DNA methylation, or both (epigenetic subclones). Some subclones may acquire mutations in epigenetic modifying proteins resulting in emergence of epigenetic changes (genetic/epigenetic subclones). Either genetic or epigenetic subclones can exhibit different functional attributes from the parental clone in terms of self-renewing capacity, drug tolerance or metastatic potential. Thus, both genetic and epigenetic mechanisms contribute to the intra-tumoral heterogeneity.