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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 47; pp. E6496 - E6505
• Main 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.11.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Aged; Base Sequence; Biological Evolution; Biological Sciences; Cell Count; Cell Line, Tumor; Cells; Clone Cells; Cloning; Computer Simulation; Deoxyribonucleic acid; DNA; Evolution; Gene Library; Genes, Neoplasm; Genetic diversity; Genetic Variation; Genotype; Humans; Male; Microdissection; Models, Genetic; Molecular Sequence Data; Mutation; Mutation Rate; Neoplasms - genetics; Neoplasms - pathology; PNAS Plus; Polymorphism, Single Nucleotide - genetics; Reproducibility of Results; Selection, Genetic; Sequence Analysis, DNA; Tumors; genetic diversity; neutral evolution; intratumor heterogeneity; natural selection; cancer evolution
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1519556112

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,M ALL(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.