Figure 1 from Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

Genetic profile of tumor awakening in the clinical setting. A, High-depth profiling (median 105. 47×) of ER+ breast cancer (BC; estrogen receptor–positive breast cancer) late relapses using a custom targeted panel. The simplified treatment scheme of patients is shown on the left. The heat map shows the mutations in ET resistance drivers in ER+ breast cancer passing the filters for allele depth ≥20, Alternate F1R2 + F2R1 ≥4, allele frequency ≥0. 1, and consequence level of moderate or high. Time to relapse (years), recurrence in the data set, allele frequency, and relapse site are indicated. Significant genes are indicated based on dN/dS analysis from the q-value of neutrality test at the gene level (*qglobalcv ≤0. 1). B, Clinical histories of patients 2–5. The table shows age and response time to ET for each patient (letrozole). C, Scatter plots of VAF from whole-genome sequencing (WGS) data. Pairwise comparisons were done for pretreatment (diagnostic biopsies) versus progression (surgical biopsies). All patients were managed with primary endocrine therapy until progression. Labeled genes passed two filters: bona fide breast cancer drivers and ET resistance drivers in ER+ breast cancer and FATHMM significant score >0. 6 (predicted damaging). Detected variants are labeled and color-coded according to detection at diagnosis (teal), progression (magenta), or both (gray). The highlighted gene (TP53) is annotated as a variant detected in ET resistance drivers in ER+ breast cancer according to the comprehensive ET-resistance driver gene list compiled based on Bertucci et al. (14). Marginal histograms of VAFs are shown on the sides of each plot. D, Spatial transcriptomics analysis of patients 1–3. On the left, representative images of regions of interest (ROI) from patient 3, pre- and post-treatment, are shown with the relevant staining. Green, pan cytokeratin (CK+) ; yellow, immune cells (CD45+) ; purple, stroma. On the right side, GeoMx UMAPs of previously identified pre-adapted SWNE up and down signatures from (2), and G2–M checkpoint signatures are shown for patients 1–3 (CK+ segment). D1 L biopsy was not suitable for spatial transcriptomics analysis due to poor specimen quality and was excluded from further examinations. S1L: surgical biopsy in the left breast; S1R: surgical biopsy in the right breast; R1R: loco-regional relapse after surgery in the right breast.