Frank, S. A. and Yanai, I. 2024. The origin of novel traits in cancer. (submitted)

The traditional view of cancer emphasizes a genes-first process. Novel cancer traits arise by genetic mutations that spread to drive phenotypic change. However, recent data support a phenotypes-first process, in which nonheritable cellular variability creates novel traits that later become heritably stabilized by genetic and epigenetic changes. Single-cell measurements support the idea that phenotypes often lead genotypes. Cancer evolution typically follows normal developmental plasticity, sometimes recombining parts of different cellular developmental programs to create novelty. In parallel, studies in evolutionary biology also support a phenotypes-first process, driven by developmental plasticity and developmental recombination. These advances in cancer research and evolutionary biology mutually reinforce a revolution in our understanding of how organisms evolve novel traits in response to new environmental challenges.