Abstract
BackgroundColorectal cancer (CRC) cell lines are widely used pre-clinical model systems. Comprehensive insights into their molecular characteristics may improve model selection for biomedical studies.MethodsWe have performed DNA, RNA and protein profiling of 34 cell lines, including (i) targeted deep sequencing (n = 612 genes) to detect single nucleotide variants and insertions/deletions; (ii) high resolution DNA copy number profiling; (iii) gene expression profiling at exon resolution; (iv) small RNA expression profiling by deep sequencing; and (v) protein expression analysis (n = 297 proteins) by reverse phase protein microarrays.ResultsThe cell lines were stratified according to the key molecular subtypes of CRC and data were integrated at two or more levels by computational analyses. We confirm that the frequencies and patterns of DNA aberrations are associated with genomic instability phenotypes and that the cell lines recapitulate the genomic profiles of primary carcinomas. Intrinsic expression subgroups are distinct from genomic subtypes, but consistent at the gene-, microRNA- and protein-level and dominated by two distinct clusters; colon-like cell lines characterized by expression of gastro-intestinal differentiation markers and undifferentiated cell lines showing upregulation of epithelial-mesenchymal transition and TGFβ signatures. This sample split was concordant with the gene expression-based consensus molecular subtypes of primary tumors. Approximately ¼ of the genes had consistent regulation at the DNA copy number and gene expression level, while expression of gene-protein pairs in general was strongly correlated. Consistent high-level DNA copy number amplification and outlier gene- and protein- expression was found for several oncogenes in individual cell lines, including MYC and ERBB2.ConclusionsThis study expands the view of CRC cell lines as accurate molecular models of primary carcinomas, and we present integrated multi-level molecular data of 34 widely used cell lines in easily accessible formats, providing a resource for preclinical studies in CRC.
Highlights
Colorectal cancer (CRC) cell lines are widely used pre-clinical model systems
Integration of DNA copy number and gene expression data We explored the influence of in-cis copy number aberrations on gene expression by testing for differences in gene expression among CNA groups
We looked for concurrent CNAs and gene expression events by retrieving genes for which the minimum/maximum CNA value and gene expression value belonged to the same cell line
Summary
Colorectal cancer (CRC) cell lines are widely used pre-clinical model systems. Comprehensive insights into their molecular characteristics may improve model selection for biomedical studies. At the DNA level, this includes the genomic instability phenotypes microsatellite instability (MSI) and chromosomal instability (CIN), as well as the epigenomic CpG island methylator phenotype (CIMP). MSI tumors have errors in the mismatch repair machinery and display numerous single nucleotide variants (SNVs) and insertions/deletions (indels) [1]. CIN tumors typically display aneuploidy with structural and/or numerical aberrations, but the underlying cause(s) remains undetermined [2]. CIMP tumors overlap to a large extent with MSI and are characterized by widespread hypermethylation of CpG islands [3, 4]
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