Functional versus non-functional intratumor heterogeneity in cancer

Abstract

Next-generation sequencing data from human cancers are often difficult to interpret within the context of tumor evolution. We developed a mathematical model describing the accumulation of mutations under neutral evolutionary dynamics and showed that 323/904 cancers (∼30%) from multiple types were consistent with the neutral model of tumor evolution.

Keywords: Cancer genome; intratumor heterogeneity; mathematical model; mutation rate; neutral expansion; site-frequency spectrum.

Figure 1.

Mutations and their frequency determine the history of individual tumors. (A) Mutations label distinct lineages and as a tumor grows the size of these lineages becomes progressively smaller. Here, with one mutation per division and all cells growing at the same rate, the 2 mutations occurring during the first division are each present in 50% of the population, whereas mutations occurring during the final division are present in 12.5%. (B) When sequencing tumor biopsies we measure the frequency f of mutations in the population. Neutral tumor evolution imprints a characteristic 1/f signature in the distribution of subclonal mutant allele frequencies.