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Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity.

Authors
  • Liu, Sixue1
  • Yang, Zuyu2
  • Li, Guanghao1
  • Li, Chunyan1
  • Luo, Yanting1
  • Gong, Qiang3
  • Wu, Xin3
  • Li, Tao1
  • Zhang, Zhiqian4
  • Xing, Baocai5
  • Xu, Xiaolan6
  • Lu, Xuemei7
  • 1 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. , (China)
  • 2 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Invasive Pathogens Laboratory, Institute of Environmental Science and Research, Porirua 5022, Wellington, New Zealand. , (China)
  • 3 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. , (China)
  • 4 Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research, Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China. , (China)
  • 5 Department of Hepatobiliary Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China. , (China)
  • 6 National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected] , (China)
  • 7 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Genomics, proteomics & bioinformatics
Publication Date
Mar 20, 2020
Identifiers
DOI: 10.1016/j.gpb.2018.07.008
PMID: 32205176
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse. Copyright © 2020. Published by Elsevier B.V.

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