<p>Chromothripsis and corresponding cancer gene amplifications and losses. <b>A,</b> Representative Circos plots of SVs and CNAs across the genome by WGS. Outer band shows an ideogram of chromosome positions and cytogenetic bands. Second band depicts total CN, and third band shows minor allele CN. The inner circle depicts SVs as arcs connecting the two relevant genomic points as identified by three algorithms (see “Methods”). CNAs in key cancer genes in the regions of chromothripsis (red, amplifications; blue, deletions) are displayed. Circos plots for all cases are shown in Supplementary Fig. S6. <b>B,</b> CN log ratio plots from the FACETS algorithm displaying the distinctive oscillating CN states on chromosomes with chromothripsis. CN segments are shown in red. Focal segments (<2 MB in size) are shown as enlarged points for visual purposes. Selected amplifications are indicated (yellow). <b>C,</b> Summary of chromosomal location of chromothriptic events in cases analyzed by WGS and tNGS. Also shown are selected amplifications and losses in oncogenes and tumor suppressors, respectively, localized to the chromothriptic chromosomes. Full list is provided in Supplementary Table S7. <b>D,</b> Schematic summary for the rate of major genomic mechanisms detected in the set analyzed by WGS (<i>n</i> = 11) and in the full cohort (<i>n</i> = 20). In the lower diagram, major chromosomes involved by chromothripsis are indicated in the inner doughnut, and corresponding recurrent gene amplifications are indicated in the outer doughnut. <b>E,</b> Total number of SVs identified in samples analyzed by WGS. Variants are color-coded by type. <b>F,</b> Number of fusions predicted in samples with available RNA-seq. <b>G,</b> Diagram illustrating putative enhancer hijacking in case A17 with chromothripsis on chromosome 2 resulting in translocation between <i>SH3RF3</i> on chromosome 2 and upstream regulatory region of <i>CCND1</i> on chromosome 11. Epigenetic landscape surrounding the breakpoint was extrapolated from data from multiple tissue types (Epilogos search tool). ChrT, chromothripsis.</p>
<p>File containing Supplementary Methods, Legends for Supplementary Tables S1-S2, Legends for Supplementary Figures S1-S4 and Legends for the Supplementary Data File 1.</p>
<p>Supplemental Materials and Methods and Materials present a complete description of methods, reagents, and statistics required to reproduce the experiments in the paper.</p>
<p>Supplementary Figure S1. ER, PR, and HER2 mRNA and protein levels across endocrine-sensitive (parental) and endocrine-resistant BC cell lines. Supplementary Figure S2. Reduced sensitivity to CDK4/6 inhibition is associated with IFN-signaling in ER+ and endocrine-resistant derivative BC cell lines. Supplementary Figure S3. The cyclin D-CDK4/6-Rb axis is altered in ER+ cell lines with acquired resistance to palbociclib. Supplementary Figure S4. Effect of acute IFN-signaling activation on sensitivity to palbociclib in ER+ BC cell lines. Supplementary Figure S5. Proteomic profiles of MCF7 P, MCF7 EDR, and their PalboR derivatives. Supplementary Figure S6. Relationship between IFN-signaling and Rb status in ER+/HER2- BC. Supplementary Figure S7. DNMT1 mRNA levels in palbociclib-sensitive and PalboR MCF7 and T47D cell lines. Supplementary Figure S8. Mutations of DNA damage response genes are not associated with IFN-signaling in ER+ BC. Supplementary Figure S9. Levels of ER and ER signalling in palbociclib-sensitive and PalboR MCF7 and T47D cell lines. Supplementary Figure S10. HALLMARK gene sets significantly up-regulated in ER+/HER2- BC patients stratified by the status (+/-) of RBsig and IRPS. Supplementary Figure S11. Impact of selected IRPS genes on relapse-free survival of ER+ BC patients.</p>
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