Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Abstract

The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

“…5 for t ∈ [0, 10] or Fig. 6 for t ∈ [100, 300]), is consistent with experimental studies on the spatial relationship between clonal sub-populations of hepatocellular carcinoma (HCC) tumour (Ling et al, 2015). In this experimental study, the authors investigated the clonal diversity of a HCC-15 tumour (and the spatial distribution of these clones), and showed the ancestral clones being positioned in the middle of the tumour, with the descendant clones radiating outward.…”

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

“…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

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”