| Title | Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution |
| Authors | Ling, Shaoping Hu, Zheng Yang, Zuyu Yang, Fang Li, Yawei Lin, Pei Chen, Ke Dong, Lili Cao, Lihua Tao, Yong Hao, Lingtong Chen, Qingjian Gong, Qiang Wu, Dafei Li, Wenjie Zhao, Wenming Tian, Xiuyun Hao, Chunyi Hungate, Eric A. Catenacci, Daniel V. T. Hudson, Richard R. Li, Wen-Hsiung Lu, Xuemei Wu, Chung-I |
| Affiliation | Univ Chinese Acad Sci, Beijing Inst Genom, Chinese Acad Sci, China Gastrointestinal Canc Res Ctr,Key Lab Genom, Beijing 100101, Peoples R China. Sun Yat Sen Univ, Coll Ecol & Evolut, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China. Peking Univ, Key Lab Carcinogenesis & Translat Res, Canc Hosp, Beijing 100142, Peoples R China. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Hematol Oncol Sect, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. Acad Sinica, Biodivers Res Ctr, Taipei 11529, Taiwan. |
| Keywords | intratumor heterogeneity genetic diversity neutral evolution cancer evolution natural selection INTRATUMOR HETEROGENEITY CLONAL EVOLUTION POPULATION-GENETICS MOLECULAR EVOLUTION CANCER EVOLUTION SEQUENCING DATA NEUTRAL THEORY BREAST-CANCER MUTATIONS SELECTION |
| Issue Date | 2015 |
| Publisher | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
| Citation | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2015,112,(47),E6496-E6505. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/416833 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.1519556112 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 北京肿瘤医院 |
