Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6496-505. doi: 10.1073/pnas.1519556112. Epub 2015 Nov 11.

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

Author information

1
Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, People's Republic of China;
2
State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China;
3
Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing 100142, People's Republic of China;
4
Department of Pediatrics, University of Chicago, Chicago, IL 60637;
5
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637;
6
Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637;
7
Biodiversity Research Center, Academia Sinica, Taipei 11529, Taiwan ciwu@uchicago.edu whli@gate.sinica.edu.tw luxm@big.ac.cn.
8
Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, People's Republic of China; ciwu@uchicago.edu whli@gate.sinica.edu.tw luxm@big.ac.cn.
9
Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, People's Republic of China; State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China; Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637; ciwu@uchicago.edu whli@gate.sinica.edu.tw luxm@big.ac.cn.

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.

KEYWORDS:

cancer evolution; genetic diversity; intratumor heterogeneity; natural selection; neutral evolution

PMID:
26561581
PMCID:
PMC4664355
DOI:
10.1073/pnas.1519556112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center