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. 2021 Sep 22;12(2):542–561. doi: 10.1158/2159-8290.CD-20-1826

Figure 3.

Figure 3. The MetHigh phenotype is associated with focal, high-amplitude Myc amplifications and elevated expression. A, Schematic representation of focal amplifications identified in profiled primary tumors. Vertical gray line denotes the location of amplicon and likely driver gene. B, Zoomed-in schematic representation of three identified Myc amplicons in MetHigh tumors illustrating the focal and high-amplitude nature of the event (left). Each event (amplicon) is illustrated by a different colored segment line. The shared amplified region between the different amplicons is denoted by the chromosomal cytoband top of panel and illustrated in a UCSC Genome Browser view (right) with RefSeq genes, including Myc, illustrated. C, Box-and-whisker plot showing Myc mRNA levels in MetHigh tumors (n = 7) and paired metastases (n = 34) compared with MetLow tumors (n = 13). FPKM, fragments per kilobase of exon per million. D, Volcano plot illustrating genes meeting cutoffs for differential expression [log fold change (logFC) >1, Padj. < 0.05] between MetHigh and MetLow tumors (n = 20 tumors used in the comparison). Genes upregulated in MetHigh tumors are highlighted in green, and genes upregulated in MetLow tumors are highlighted in red. E, Top 10 hallmark gene sets identified as enriched in MetHigh tumors compared with MetLow tumors using all differentially expressed genes (DEG; Padj. < 0.05). F, Top five transcription factor (TF) binding sites enriched in DEGs in MetHigh tumors compared with MetLow tumors (Padj. < 0.05) identified by Metacore prediction software. G, Heat map showing unsupervised clustering of DEGs (logFC >1, Padj. < 0.05) between MetHigh and MetLow tumors (n = 20) and their association with PDAC transcriptional subtypes previously reported by Collisson and colleagues (42), Moffitt and colleagues (15), and Bailey and colleagues (16). ADEX, aberrantly differentiated endocrine exocrine; QM-PDA, quasi-mesenchymal-pancreatic ductal adenocarcinoma. H, Kaplan–Meier analysis showing overall survival of patients with PDAC in the TCGA cohort stratified into those with a MetHigh signature (red line) versus those with a MetLow signature (green line). Signature based on DEGs with absolute logFC >0.58 and Padj. < 0.05 (736 up- and 1,036 downregulated genes). Statistical analysis in C was performed by Wilcoxon test (*, P = 3.9 × 10−4; **, P = 5.3 × 10−5). Box and whiskers represent median mRNA expression and interquartile range. Statistical analysis in H was performed by log-rank test.

The MetHigh phenotype is associated with focal, high-amplitude Myc amplifications and elevated expression. A, Schematic representation of focal amplifications identified in profiled primary tumors. Vertical gray line denotes the location of amplicon and likely driver gene. B, Zoomed-in schematic representation of three identified Myc amplicons in MetHigh tumors illustrating the focal and high-amplitude nature of the event (left). Each event (amplicon) is illustrated by a different colored segment line. The shared amplified region between the different amplicons is denoted by the chromosomal cytoband top of panel and illustrated in a UCSC Genome Browser view (right) with RefSeq genes, including Myc, illustrated. C, Box-and-whisker plot showing Myc mRNA levels in MetHigh tumors (n = 7) and paired metastases (n = 34) compared with MetLow tumors (n = 13). FPKM, fragments per kilobase of exon per million. D, Volcano plot illustrating genes meeting cutoffs for differential expression [log fold change (logFC) >1, Padj. < 0.05] between MetHigh and MetLow tumors (n = 20 tumors used in the comparison). Genes upregulated in MetHigh tumors are highlighted in green, and genes upregulated in MetLow tumors are highlighted in red. E, Top 10 hallmark gene sets identified as enriched in MetHigh tumors compared with MetLow tumors using all differentially expressed genes (DEG; Padj. < 0.05). F, Top five transcription factor (TF) binding sites enriched in DEGs in MetHigh tumors compared with MetLow tumors (Padj. < 0.05) identified by Metacore prediction software. G, Heat map showing unsupervised clustering of DEGs (logFC >1, Padj. < 0.05) between MetHigh and MetLow tumors (n = 20) and their association with PDAC transcriptional subtypes previously reported by Collisson and colleagues (42), Moffitt and colleagues (15), and Bailey and colleagues (16). ADEX, aberrantly differentiated endocrine exocrine; QM-PDA, quasi-mesenchymal-pancreatic ductal adenocarcinoma. H, Kaplan–Meier analysis showing overall survival of patients with PDAC in the TCGA cohort stratified into those with a MetHigh signature (red line) versus those with a MetLow signature (green line). Signature based on DEGs with absolute logFC >0.58 and Padj. < 0.05 (736 up- and 1,036 downregulated genes). Statistical analysis in C was performed by Wilcoxon test (*, P = 3.9 × 10−4; **, P = 5.3 × 10−5). Box and whiskers represent median mRNA expression and interquartile range. Statistical analysis in H was performed by log-rank test.