Article Figures & Data
Figures
- Figure 1. All basal cell carcinoma (BCC) versus normal skin samples: up-regulated.
(A) Unsupervised hierarchical clustering based on the top 50 most up-regulated genes in all BCCs (pink) versus normal skin controls (blue). A color key refers to gene expression in normalized log2 (pseudocounts). (B) Selected up-regulated KEGG pathways in BCC compared with normal skin. A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. (C, D) Up-regulated genes in BCC overlaid on KEGG “IL-17 signalling pathway” (C) and “basal cell carcinoma” (D). In red are significant target genes. (E) Violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for all BCC (red) versus normal skin (turquoise). From left to right and top to bottom, plots for PTCH1, FOXI3, LEF1, FZD8, MMP1, and PCDH11X are displayed. Q-values are displayed.
- Figure S1. Up-regulated genes in basal cell carcinoma compared with normal skin, overlaid on the KEGG “Pathways in Cancer” pathway.
In red are significant target genes. Multiple hypothesis-corrected P-value was P = 3.9 × 10−03.
- Figure S2. Up-regulated PANTHER pathways in basal cell carcinoma compared with normal skin.
A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. Refer to Table S4 for full results.
- Figure 2. All basal cell carcinomas (BCCs) versus normal skin samples: down-regulated.
(A) Selected down-regulated KEGG pathways in BCC compared with normal skin. A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. (B, C) Down-regulated genes in BCC overlaid on KEGG “peroxisome proliferator-activated receptor signalling pathway” (B) and “Retinol metabolism in animals” (C). In red are significant target genes. (D) Violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for all BCC (red) versus normal skin (turquoise). From left to right, plots for TGM5, FLG, and LCE1C are displayed. Q-values are displayed.
- Figure 3. Quantitative reverse-transcription PCR (qRT-PCR) for selected genes in McGill basal cell carcinoma (BCC) sample cohort.
The heat map summarized the normalized enrichments for BCC samples from the McGill cohort. Normalized enrichment ratios (to housekeeping genes and to normal skin samples) are plotted. A normalized enrichment ratio of 1 indicates no enrichment over normal skin controls after normalization using housekeeping genes. A color key refers to the normalized enrichment ratio along predetermined ranges (<1 = blue; >1 = red). BCC patient samples are represented by their anonymous identifier on the x-axis and tested genes are on y-axis (Table S7).
- Figure S3. Receiver operator curves (ROC) for experimental validation.
(A, B) Receiver operator curves based on gene expression results from the McGill basal cell carcinoma sample cohort for (A) a combined approach based on 19 diverse biomarkers (see Results section) and (B) 19 individual genes. AUC, area under curve.
- Figure 4. High-risk basal cell carcinomas (BCCs) versus low-risk BCCs based on histopathological subtypes with aggressive features.
(A) Unsupervised hierarchical clustering based on up-regulated genes in high-risk BCC subtypes (pink) versus low-risk BCC subtypes (blue). A color key refers to gene expression in normalized log2 (pseudocounts). (B, C) Selected enriched molecular function (B) and biological process (C) Gene Ontology terms from up-regulated genes in high-risk BCCs based solely on histopathological subtypes. A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. (D) Representative violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for high-risk BCC subtypes (red) versus low-risk BCC subtypes (turquoise). From left to right, plots for FIBIN, CSNK2B, and BCAT1 are displayed. Q-values are displayed.
- Figure 5. Advanced versus non-advanced basal cell carcinomas (BCCs).
(A) Unsupervised hierarchical clustering based on the top 50 most up-regulated genes in advanced BCCs (pink) versus non-advanced BCCs (blue). A color key refers to gene expression in normalized log2 (pseudocounts). (B) Selected up-regulated KEGG pathways in advanced BCCs compared to non-advanced BCC. A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. (C, D) Up-regulated genes in advanced BCCs overlaid on KEGG “PI3K/Akt signalling pathway” (C) and “TLR signalling pathway” (D). In red are significant target genes. (E) Violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for advanced BCC (red) versus non-advanced BCC (turquoise). From left to right and top to bottom, plots for TLR4, TGFB1, PIK3AP1, and PDGFRA are displayed. Q-values are displayed.
- Figure S4. Up-regulated genes in advanced basal cell carcinoma overlaid on the KEGG “extracellular matrix–receptor interactions” pathway.
In red are significant target genes. Multiple hypothesis-corrected P-value was P = 1.4 × 10−08.
- Figure S5. Up-regulated PANTHER pathways in advanced basal cell carcinoma.
A false discovery rate Q-value cutoff < 0.05 was used. The logarithm of negative (Q-value) is plotted. Refer to Table S13 for full results.
- Figure 6. Vismodegib-resistant versus vismodegib-sensitive basal cell carcinomas (BCCs).
(A) Unsupervised hierarchical clustering based on all differentially regulated (up and down) genes in vismodegib-resistant BCCs (pink) versus vismodegib-sensitive BCCs (blue). A color key refers to gene expression in normalized log2 (pseudocounts). (B) Up-regulated BioCarta pathways in vismodegib-resistant BCCs compared with vismodegib-sensitive BCCs. A false discovery rate Q-value cutoff <0.05 was used. The logarithm of negative (Q-value) is plotted. (C) Violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for vismodegib-resistant (red) versus vismodegib-sensitive BCCs (turquoise). From left to right and top to bottom, plots for DACT1, EDAR, FSTL1, and PDGFC are displayed. Q-values are displayed. (D) Violin plots representing the distribution of gene expression, shown in log2 (pseudocounts), for vismodegib-resistant (red) versus vismodegib-naïve (untreated) BCCs (turquoise). From left to right, plots for DACT1 and FSTL1 are displayed. Q-values are displayed. Please note that in (D), vismodegib-naïve tumors are displayed as a comparative group.
- Figure 7. Summary of differentially regulated and potentially targetable pathways in basal cell carcinoma (BCC).
(A) Summary of enriched differentially regulated pathways and/or genes for all BCCs versus normal skin (top panel), high-risk versus low-risk BCCs (second top panel), advanced versus non-advanced BCCs (second bottom panel), and vismodegib-resistant versus vismodegib-sensitive BCCs (bottom panel). Scale bars on schematized histology sections represent approximately 200 μm. (B) Potential therapeutic targets for BCCs in select signalling pathways. Asterisks indicate specific molecules for which agents are either available or under development.
- Figure S6. Transcript integrity number (TIN) analysis.
(A, B, C, D) Median Transcript Integrity Number (medTIN) for normal skin versus basal cell carcinoma (BCC) (A), low-risk versus high-risk BCC based solely on histopathological subtypes with aggressive features (B), non-advanced versus advanced BCC (C), and vismodegib-sensitive versus vismodegib-resistant BCC (D). P-values were calculated with the nonparametric Whitney–Mann U test.
- Figure S7. Tumor purity determined by the ESTIMATE algorithm based on gene expression for aggressive basal cell carcinoma (BCC) (advanced BCC + high-risk BCC based on histopathological types) versus non-aggressive BCC (low-risk BCC based on histopathological types).
P-value was calculated with the nonparametric Whitney–Mann U test.
- Figure S8. Principal component analysis based on gene expression data and tumor purity.
(A, B, C, D) Principal component analysis plots of gene expression data and tumor purity (components 1 and 2) for various comparisons (A, B, C, D). Samples with higher tumor purity are plotted with increasingly larger points, according to the following purities: <50%, 50–60%, 60–70%, 70–80%, 80–90%, and >90%.
Supplementary Materials
Table S1 Study characteristics.
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