Mutation-Selection Balance and Compensatory Mechanisms in Tumor Evolution

Intratumor heterogeneity and phenotypic plasticity, mediated by a range of somatic aberrations, metabolic and epigenetic adaptations, are the principal mechanisms that enable cancers to evolve resistance to treatment and survive under environmental stress. Nonetheless, a comprehensive picture of the interplay between different somatic aberrations across scales, from point mutations to whole-genome duplications, in tumor initiation and progression is lacking. Here we explore the temporal behavior of each type of aberration, how it is affected by selection, and how it affects patients’ clinical outcome. The dependency of tumor fitness on the levels of different aberrations is biphasic such that there is an optimal value for each type of change. These optima are attained in different phases of tumor evolution and appear to play compensatory roles in maintaining tumor fitness. Specifically, repeat instability contributes to cancer initiation, whereas larger aberrations (e.g., aneuploidy) are progressively involved in later stages. Consideration of the impact of environmental factors on the emergence of genetic aberrations further supports this temporal order. A better understanding of the interactions between genetic aberrations, the microenvironment and epigenetic and metabolic cellular states is essential for early detection, prevention, and development of therapeutic strategies.