Multiple mutations within individual oncogenes.

Recent studies of the cancer genome have identified numerous patients harboring multiple mutations (MM) within individual oncogenes. These MM (de novo MM) in cis synergistically activate the mutated oncogene and promote tumorigenesis, indicating a positive epistatic interaction between mutations. The relatively frequent de novo MM suggest that intramolecular positive epistasis is widespread in oncogenes. Studies also suggest that negative and higher-order epistasis affects de novo MM. Comparison of de novo MM and MM associated with drug-resistant secondary mutations (secondary MM) revealed several similarities with respect to allelic configuration, mutational selection and functionality of individual mutations. Conversely, they have several differences, most notably the difference in drug sensitivities. Secondary MM usually confer resistance to molecularly targeted therapies, whereas several de novo MM are associated with increased sensitivity, implying that both can be useful as therapeutic biomarkers. Unlike secondary MM in which specific secondary resistant mutations are selected, minor (infrequent) functionally weak mutations are convergently selected in de novo MM, which may provide an explanation as to why such mutations accumulate in cancer. The third type of MM is MM from different subclones. This type of MM is associated with parallel evolution, which may contribute to relapse and treatment failure. Collectively, MM within individual oncogenes are diverse, but all types of MM are associated with cancer evolution and therapeutic response. Further evaluation of oncogenic MM is warranted to gain a deeper understanding of cancer genetics and evolution.