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. 2014 Mar 13;15(1):190.
doi: 10.1186/1471-2164-15-190.

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma

John C Castle  1 , Martin Loewer, Sebastian Boegel, Jos de Graaf, Christian Bender, Arbel D Tadmor, Valesca Boisguerin, Thomas Bukur, Patrick Sorn, Claudia Paret, Mustafa Diken, Sebastian Kreiter, Özlem Türeci, Ugur Sahin
Affiliations

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma

John C Castle et al. BMC Genomics. .

Abstract

Background: Tumor models are critical for our understanding of cancer and the development of cancer therapeutics. Here, we present an integrated map of the genome, transcriptome and immunome of an epithelial mouse tumor, the CT26 colon carcinoma cell line.

Results: We found that Kras is homozygously mutated at p.G12D, Apc and Tp53 are not mutated, and Cdkn2a is homozygously deleted. Proliferation and stem-cell markers, including Top2a, Birc5 (Survivin), Cldn6 and Mki67, are highly expressed while differentiation and top-crypt markers Muc2, Ms4a8a (MS4A8B) and Epcam are not. Myc, Trp53 (tp53), Mdm2, Hif1a, and Nras are highly expressed while Egfr and Flt1 are not. MHC class I but not MHC class II is expressed. Several known cancer-testis antigens are expressed, including Atad2, Cep55, and Pbk. The highest expressed gene is a mutated form of the mouse tumor antigen gp70. Of the 1,688 non-synonymous point variations, 154 are both in expressed genes and in peptides predicted to bind MHC and thus potential targets for immunotherapy development. Based on its molecular signature, we predicted that CT26 is refractory to anti-EGFR mAbs and sensitive to MEK and MET inhibitors, as have been previously reported.

Conclusions: CT26 cells share molecular features with aggressive, undifferentiated, refractory human colorectal carcinoma cells. As CT26 is one of the most extensively used syngeneic mouse tumor models, our data provide a map for the rationale design of mode-of-action studies for pre-clinical evaluation of targeted- and immunotherapies.

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Figures

Figure 1
Figure 1
The CT26 Genome. A) Circos diagram showing (outer to inner): cytogenetic bands in black, gray and white. Track 1: DNA copy number. Black: deleted; green: haploid; yellow: diploid; dark purple: triploid; light purple: tetraploid; dark blue: pentaploid; bright blue: hexaploid; red: higher copy number. Track 2: High confidence point mutations, plotted based on DNA allele frequency. Inner is allele frequency 0, outer is allele frequency 100. Colors are blue (0–40), green (40–60), orange (60–90), and red (90–100). Track 3: predicted MHC binding IC50 scores for missense mutations. Mutations in peptides likely to bind MHC are colored orange (IC50 < 500 nM). Track 4: insertions and deletions plotted according to allele frequency. B) DNA gene copy number. C) Single nucleotide mutation changes and the nucleotide immediately 3′ of the mutation. D) Mutation classification.
Figure 2
Figure 2
Gene expression of onco-relevant genes, stem cell and proliferation markers, WNT signaling pathway genes, EMT and epithelial markers, and differentiation markers in CT26 and mouse colon. Error bars represent the maximum and minimum values for the CT26 triplicates and the six normal colon samples (triplicates of one male and triplicates of one female mouse).
Figure 3
Figure 3
Reactome pathways over-expressed in CT26 versus normal colon. Enriched Reactome pathways are displayed using Cytoscape ClueGO. Ribosomal associated genes are over-expressed in CT26; while they are part of the influenza gene set, we posit their over-expression reflects increased translational activity rather than an influenza-related process. For each gene set, Cytoscape ClueGo calculates a false-discovery rate statistic (FDR q-value) reflecting the likelihood of the given enrichment by chance: the pathways listed in the table those with a zero q-value. Each dot in the image represents a separate Reactome gene set. Gene sets with common members are placed proximally, grouped into common themes, colored the same and labeled. Q-values for enriched pathways, Cytoscape settings and gene membership are in the supplementary information.
Figure 4
Figure 4
Gene sets over-expressed in CT26 versus normal colon. A). The top 10 over-expressed gene sets. Gene sets included those curated from literature and overexpression was determined using GenePattern [47]. B-F): gene set enrichment for the targets of specific genes, including the GenePattern enrichment plot showing the enrichment plot (green) and the location of the individual gene set members in the expression ranked-ordered list (black vertical lines). The plot on the right (blue bars) shows the expression of the targeting gene RB1 (B), E2H2 (C), LIN9 (D), FOXO3 (E) and E2F1 (F).
Figure 5
Figure 5
MHC class I (H-2D, H2-K, H-2 L) and class II (H2-IA) expression in normal mouse tissues and CT26 cells. The normal tissues are from both C57BL/6 J and BALB/c. The C57BL/6 J genome does not have the H-2 L locus.
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