Signatures Of Neutral Evolution In Exponentially Growing Tumors: A Theoretical Perspective

Author summaryFor many years, the dominant paradigm was that cancers evolve by a succession of selective sweeps in which new fitter mutants take over the system. About five years ago, Sottoriva et al introduced the Big Bang model of cancer initiation, which postulated that all the mutations needed were present when the tumor started growing. A consequence of this viewpoint is that mutations in the growing tumor are neutral. Many researchers have objected to this conclusion for a wide variety of reasons. Here, we use mathematical analysis to show that with enough sequence data the site frequency spectrum can be used to distinguish neutral evolution from the two-phase model of clonal evolution. This conclusion differs from previously published simulation results.Recent work of Sottoriva, Graham, and collaborators have led to the controversial claim that exponentially growing tumors have a site frequency spectrum that follows the 1/f law consistent with neutral evolution. This conclusion has been criticized based on data quality issues, statistical considerations, and simulation results. Here, we use rigorous mathematical arguments to investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are lambda(0) < lambda(1), then the site frequency spectrum is c/f(alpha) where alpha = lambda(0)/lambda(1). This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/f law. Our results show that, in contrast to published criticisms, neutral evolution in an exponentially growing tumor can be distinguished from the two-type model using the site frequency spectrum.