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.

Publication date: Mar 20, 2020

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.

Open Access PDF

Liu, S., Yang, Z., Li, G., Li, C., Luo, Y., Gong, Q., Wu, X., Li, T., Zhang, Z., Xing, B., Xu, X., and Lu, X. Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity. 06563. 2020 Genomics Proteomics Bioinformatics.

Concepts Keywords
Clone Neoplasm
Epigenetic Carcinogenesis
Genetic Epigenetics
Genetic Diversity Proteomics
Genome DNA methylation
Germline Tumour heterogeneity
Hepatocellular Carcinoma Epigenomics
Metastasis DNA
Methylation Oncology
Nucleotide Cancer
Omics Medicine
Personalized Medicine Genetics
Phenotypic Branches of biology
Phylogenetic Diversity tumor
Proteomics Individual tumor
Relapse Heterogeneous SNVs tumor
Sequencing Plausible determinants metastasis
Tumor
Tumorigenesis
Vivo

Semantics

Type Source Name
disease MESH tumorigenesis
disease MESH tumor
disease MESH hepatocellular carcinoma
pathway KEGG Hepatocellular carcinoma
disease MESH metastasis
disease MESH relapse

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *