Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 47, Pages E6496-E6505Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519556112
Keywords
intratumor heterogeneity; genetic diversity; neutral evolution; cancer evolution; natural selection
Categories
Funding
- National Basic Research Program (973 Program) of China [2014CB542006]
- Chinese Academy of Sciences [XDB13040300, KJZD-EW-L06-1]
- National Science Foundation of China [91131903, 31301036, 91231204]
- National High-Tech R&D Program (863 Program) of China [2012AA022502]
- 985 Project [33000-18811202]
- Science Foundation of State Key Laboratory of Biocontrol [SKLBC15A37]
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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.
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