title: 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.
authors.affiliation: 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;
authors.forename: Shaoping
authors.initials: S
authors.lastname: Ling
authors.affiliation: 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;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: 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;
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: 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;
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: 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;
authors.forename: Yawei
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China;
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.affiliation: 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;
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Lili
authors.initials: L
authors.lastname: Dong
authors.affiliation: 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;
authors.forename: Lihua
authors.initials: L
authors.lastname: Cao
authors.affiliation: 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;
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.affiliation: 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;
authors.forename: Lingtong
authors.initials: L
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China;
authors.forename: Qingjian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gong
authors.affiliation: 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;
authors.forename: Dafei
authors.initials: D
authors.lastname: Wu
authors.affiliation: 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;
authors.forename: Wenjie
authors.initials: W
authors.lastname: Li
authors.affiliation: 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;
authors.forename: Wenming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing 100142, People's Republic of China;
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Tian
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing 100142, People's Republic of China;
authors.forename: Chunyi
authors.initials: C
authors.lastname: Hao
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL 60637;
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hungate
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637;
authors.forename: Daniel V T
authors.initials: DV
authors.lastname: Catenacci
authors.affiliation: Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637;
authors.forename: Richard R
authors.initials: RR
authors.lastname: Hudson
authors.affiliation: Biodiversity Research Center, Academia Sinica, Taipei 11529, Taiwan ciwu@uchicago.edu whli@gate.sinica.edu.tw luxm@big.ac.cn.
authors.forename: Wen-Hsiung
authors.initials: WH
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Wu
mesh_terms: D000368:Aged; D001483:Base Sequence; D005075:Biological Evolution; D002452:Cell Count; D045744:Cell Line, Tumor; D002999:Clone Cells; D003198:Computer Simulation; D015723:Gene Library; D052138:Genes, Neoplasm; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D042282:Microdissection; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
keywords: cancer evolution; genetic diversity; intratumor heterogeneity; natural selection; neutral evolution