Figure 1 from Multistate Gene Cluster Switches Determine the Adaptive Mitochondrial and Metabolic Landscape of Breast Cancer

Large-scale transcriptome switches identify breast cancer subtypes. A, Gene set switch identification in bicluster samples. MCbiclust starts with a random gene set in a random sample set and performs a greedy search aiming for the sample set, across which, the gene set has the highest correlation. As the absolute value of correlation is maximized during the search, the resulting top correlating samples display two gene sets with sharp anticorrelation (switch) between them. The gene sets and sample sets can be extended to the whole transcriptome and sample set by quantifying correlations (see main text), which provides the basis for gene set enrichment analysis. B, Visualization of individual switches (MB1, MB2, MB3 biclusters) in all METABRIC samples. Two-dimensional distribution by PC1 and ranking index are shown, overlaid with PAM50 classifiers. Dashed lines represent the thresholds to include samples in the forks, calculated as 0.04 × forkscale (see Materials and Methods). C, UpSet matrix and plots of sample intersections between top and bottom positions of each bicluster switch. Unique and overlapping (intersect) samples are shown separately. D, Scheme of switches. MB1 and MB2 share their LF, thus representing a multistate switch, while MB3 is an independent bistate switch, thus the MB1_2 and MB_3 biclusters represent different switch mechanisms. E and F, Interswitch relationships are shown in two-dimensional distribution plots of samples by two biclusters (switches). The axes represent the scale between the UF and LF of each bicluster. The distribution of samples according to their MB1 vs. MB2 forkscale value (see Materials and Methods) is shown in E, while the combinations of MB3 with MB1 or MB2 are shown in F. G, Heatmap of the correlation values (CVs, Pearson r) across the whole transcriptome in the MB1 bicluster; a small set of midrange values were hidden (see gaps in heatmap). Annotations show the locations of mitochondrial and metabolic genes (top), and bicluster genes (bottom). For comparison between the switches, bottom annotation plots show the CV values of each sample in the three biclusters (switches). H, Fold enrichment of mitochondrial and metabolic (with intersections) genes in the anticorrelated gene sets. Heatmap shows enrichment values of each gene set in each position of all switches. Gene set intersections are on the Venn diagram below the heatmap.