Identification of neutral tumor evolution across cancer types

Abstract

Despite extraordinary efforts to profile cancer genomes, interpreting the vast amount of genomic data in the light of cancer evolution remains challenging. Here we demonstrate that neutral tumor evolution results in a power-law distribution of the mutant allele frequencies reported by next-generation sequencing of tumor bulk samples. We find that the neutral power-law fits with high precision 323 of 904 cancers from 14 types, selected from different cohorts. In malignancies identified as neutral, all clonal selection occurred prior to the onset of cancer growth and not in later-arising subclones, resulting in numerous passenger mutations that are responsible for intra-tumor heterogeneity. Reanalyzing cancer sequencing data within the neutral framework allowed the measurement, in each patient, of both the in vivo mutation rate and the order and timing of mutations. This result provides a new way to interpret existing cancer genomic data and to discriminate between functional and non-functional intra-tumor heterogeneity.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Specifically, while evidence for selection of driver events in cancer development, as well as the selection pressures imposed by therapy, are undisputed, following a 'big-bang' of diversity early in tumor evolution, ITH development can follow the laws of neutral growth (Sottoriva et al, 2015). In support of this, Williams and colleagues noted that, for a subset of tumors, the relationship between the number of subclonal mutations and their relative abundance was consistent with a neutral growth pattern rather than subclonal expansions (Williams et al, 2016). Likewise, in an extensively sampled colorectal cancer the degree of heterogeneity appeared more consistent with neutral growth (Ling et al, 2015), and lineage-tracing studies in mice have suggested ITH may emerge from a stem-cell hierarchy of cancer cells evolving under neutral evolution (Driessens et al, 2012).…”

“…As such, the extent to which positive selection can account for the degree of ITH in tumors has been called into question (Ling et al, 2015;Williams et al, 2016). Specifically, while evidence for selection of driver events in cancer development, as well as the selection pressures imposed by therapy, are undisputed, following a 'big-bang' of diversity early in tumor evolution, ITH development can follow the laws of neutral growth (Sottoriva et al, 2015).…”

Cancer evolution and heterogeneity

“…On the contrary, progressor alterations accumulated in few driver genes, and the passenger mutations fostered neutral evolution. According to the distribution of variant allele frequency (VAF), neutral evolution was observed in 30% of all malignancies 41. Our previous whole‐exome sequencing (WES) study by MRA showed neutral evolution in advanced CRC cases, which was validated by computational simulation analysis.…”

Functional versus non-functional intratumor heterogeneity in cancer

“…These mutations are the result of replication errors during cell division and their frequency distribution is a consequence of each cancer's evolutionary history. In our latest work 1 we utilized the distribution of mutant allele frequencies of tumors to infer how individual cancers grew.…”

“…Equation [1] has been described previously in the population genetics literature, 2,3 but has not to our knowledge been applied to cancer genomes. We tested the prediction of our model on next-generation sequencing data from 904 tumors of many different types.…”