Fig. 5
Changes in mRNA impair cell differentiation and mimic oncogenic U2AF1 inactivation in MSI CRC. A Schematic representation of the normal colonic crypt. B A total of 134 genes that overlapped between our MSI splicing signature and that of Habowski et al. that regroups alternative mRNA changes that drive cell differentiation in the normal colonic crypt [19]. SC, stem cells; Abs., absorptive; Sec., secretory/deep crypt secretory cells/goblet; EEC, enteroendocrine; Ent, enterocytes, TuftC, tuft cells. The pathway analysis of the 134 genes shows a significative enrichment in TGF-beta signaling pathway (Padj = 0.032), BioPlanet 2019. C Left panel, heatmap displaying pathway analysis of coding mutations, exon skipping signature (All, Alternative, Constitutive, DD134, ES96), and of the exon skipping + coding mutations; colors represent enrich pathway Padj, -log10. Enrichment was realized with EnrichR BioPlanet 2019. Terms were sorted by Padj (< 0.05) and regroup first in pathways (rows, right) then in groups of pathways (rows, left). Columns were sorted by enriched condition parameters. A more detail heatmap showing the different terms is available in Fig. S12. Right panel, interactions between genes related to coding repeat mutations and/or genes with alterations in the splicing of genes involved in Hippo signaling pathways which play a role in CRC and in cell differentiation in the colonic crypt (adapted from KEGG: hsa04390). D Left panel, number of neoepitopes potentially represented by HLA-MHC class I or II for each patient (n = 101 CRC MSI). Middle panel, boxplot displaying the number of unique neoepitopes in average per transcript and per patient. Right panel, boxplot displaying the number of neoepitopes showing high affinity for HLA-MHC class I or II for each patient. E Constitutive exon skipping with a frameshift (ES96) exposing a neoantigen tail; genes were ordered by mutational frequency in the early stage. F Overlapping signature of 125 exons (120 genes) containing common exons between the U2AF-S34F signature and the MSI splicing signature