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

	Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity
	Liu, SX; Yang, ZY; Li, GH; Li, CY; Luo, YT; Gong, Q; Wu, X; Li, T; Zhang, ZQ; Xing, BC; Xu, XL; Lu, XM
	2019
发表期刊	GENOMICS PROTEOMICS & BIOINFORMATICS
ISSN	1672-0229
卷号	17 期号:6 页码:576-589
摘要	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). Multiomics 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.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13153
专题	科研部门_适应性进化与进化医学（吕雪梅）昆明动物研究所
推荐引用方式 GB/T 7714	Liu, SX,Yang, ZY,Li, GH,et al. Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity[J]. GENOMICS PROTEOMICS & BIOINFORMATICS,2019,17(6):576-589.
APA	Liu, SX.,Yang, ZY.,Li, GH.,Li, CY.,Luo, YT.,...&Lu, XM.(2019).Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity.GENOMICS PROTEOMICS & BIOINFORMATICS,17(6),576-589.
MLA	Liu, SX,et al."Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity".GENOMICS PROTEOMICS & BIOINFORMATICS 17.6(2019):576-589.

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