Analysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials.

摘要: Currently, drug development efforts and clinical trials to test them are often prioritized by targeting genes with high frequencies of somatic variants among tumors. However, differences in oncogenic mutation rate-not necessarily the effect variant has on tumor growth-contribute enormously frequency. We argue that decoupling contributions cancer lineage selection frequency tumors is critical understanding-and predicting-the therapeutic potential different interventions. To provide an indicator strength potential, at which we observe a given across patients must be modulated our expectation rate target size potential. Additionally, antagonistic synergistic epistasis mutations also impacts benefit targeted development. Quantitative approaches should fostered use known genetic architectures types, decouple rate, rigorous guidance regarding investment By integrating evolutionary principles detailed mechanistic knowledge into those approaches, can maximize ability identify therapies most likely yield substantial benefit.