Mechanisms underlying cancer development by mutations in epigenetic modifiers
Image showing frequent targeting of the epigenetic machinery in human colorectal cancer (CRC). All CRCs in the Catalog of Somatic Mutations in Cancer (COSMIC) database were queried. Mutated genes were run through the Database for Annotation, Visualization and Integrated Discovery (DAVID) for ontology and pathway analysis. The top 8 functional categories are listed along with their associated p-values.
There is growing realization that genes regulating epigenetic marks are mutated at high frequency in a broad spectrum of human cancers. For example, the ten-eleven-translocation (TET) family of proteins is mutated in nearly 30 percent of myeloid malignancies. The way these mutations initiate or promote cancer is likely distinct from traditional tumor suppressor genes like p53, demanding a better mechanistic understanding of how they regulate cell growth and differentiation.
To study this process, model cell culture and animal systems are being developed to probe the impact of commonly occurring regulator epigenetic mutations on the epigenome and transcriptome levels at single genes and over the entire genome. This data is related to clinical pathologic data from patients with cancers presenting these mutations.
These studies are expected to yield novel and specific individualized treatments for cancer patients presenting mutations in epigenetic regulatory genes. The research team hypothesizes that tumors with epigenetic mutations are uniquely susceptible to drugs that target the epigenome, creating new avenues for individualized therapy.