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. 2022 Sep 8;82(21):4058–4078. doi: 10.1158/0008-5472.CAN-22-1731

Figure 6.

Figure 6. Differential expression profiles driven by KRAS G12C comutation status in LUADs. Comutation driven GSEA leveraging transcriptomic profiles from RNA sequencing revealed marked differences in gene expression programs depending on KRAS G12C comutations. A, Normalized enrichment scores from GSEA in KRAS G12C-mutant LUADs harboring different comutations were used as an input for UMAP dimensionality reduction, that revealed convergence of gene sets in distinct clusters related to immune/inflammatory response, metabolism, sustained/mitogenic signaling, oxidative phosphorylation, apoptosis, DNA maintenance, replication and repair and cell-cycle progression. B and C, KRAS G12C/KEAP1 co-mutant LUADs showed a downregulation of gene sets related to inflammatory responses, while showing an enrichment in metabolism, oxidative phosphorylation reactive oxygen species pathway gene sets. The continuous significance score (Signif) indicates the −log10(Padj) * sign(fold-change) from the GSEA, red indicates upregulation and blue indicates downregulation. D and E, A prominent upregulation of inflammatory response related gene expression programs was noted in the TME of KRAS G12C/TP53 co-mutant LUADs, together with gene sets related to cell-cycle progression and E2F-driven proliferation. Quantile-quantile plots were generated to visually compare the ranks of genes in the pathway to ranks that were sampled from a discrete uniform distribution. Adjusted P values for gene set differential expression are provided for comparison of KRAS G12C/non–RAS-mutant LUAD to KRAS G12C-mutant LUAD. LUAD, lung adenocarcinoma; HM, Hallmark; KG, Kegg.

Differential expression profiles driven by KRAS G12C comutation status in LUADs. Comutation-driven GSEA leveraging transcriptomic profiles from RNA sequencing revealed marked differences in gene expression programs depending on KRAS G12C comutations. A, Normalized enrichment scores from GSEA in KRAS G12C-mutant LUADs harboring different comutations were used as an input for UMAP dimensionality reduction, which revealed convergence of gene sets in distinct clusters related to immune/inflammatory response, metabolism, sustained/mitogenic signaling, oxidative phosphorylation, apoptosis, DNA maintenance, replication and repair, and cell-cycle progression. B and C,KRAS G12C/KEAP1 comutant LUADs showed a downregulation of gene sets related to inflammatory responses, while showing an enrichment in metabolism, oxidative phosphorylation reactive oxygen species pathway gene sets. The continuous significance score (Signif) indicates the −log10(Padj) * sign(fold-change) from the GSEA. Red, upregulation; blue, downregulation. D and E, A prominent upregulation of inflammatory response related gene expression programs was noted in the TME of KRAS G12C/TP53 comutant LUADs, together with gene sets related to cell-cycle progression and E2F-driven proliferation. Quantile-quantile plots were generated to visually compare the ranks of genes in the pathway to ranks that were sampled from a discrete uniform distribution. Adjusted P values for gene set differential expression are provided for comparison of KRAS G12C/non–RAS-mutant LUAD to KRAS G12C-mutant LUAD. HM, Hallmark; KG, Kyoto Encyclopedia of Genes and Genomes, KEGG.