Fig. 1

HR deficiency as clinically actionable feature in chordoma. a Copy number plot of patient Chord_05 showing chromosomal coordinates based on WES data (horizontal axis) and the log2 ratio of copy number changes (vertical axis). Red and black regions indicate different chromosomes. b CNA profile of patient Chord_05. Segment-wise total copy number counts after correction for TCC and ploidy are shown. c Contribution of mutational signatures (absolute exposures) to the overall SNV load in chordoma patients. Each bar represents the number of SNVs explained by the respective mutational signature in an individual tumor. Error bars represent 95% confidence intervals. Exposures for tumors analyzed by WES are displayed on the left. Exposures for tumors analyzed by WGS are displayed on the right. AC1 clock-like, spontaneous deamination; AC2 and AC13 altered APOBEC activity; AC3 defective HR; AC6 defective DNA mismatch repair; AC7 ultraviolet light exposure; AC10 altered POLE activity. d Scatter plot of measures of genomic instability (sum of HRD score and number of LSTs; vertical axis) versus exposures to signature AC3 (horizontal axis). To include both WES and WGS data, exposures to AC3 were normalized to the size of the target capture. e Therapeutic targeting of defective HR in patient Chord_05. T1-weighted, fat-saturated, post-contrast MRI at baseline 1 (left panel), after 6 months of imatinib therapy (progressive disease, baseline 2 for further follow-up; middle panel), and after 5 months of olaparib therapy (stable disease compared to baseline 2; right panel). A biopsy for WES was taken at progression (middle panel). The main bulk of the sacrococycgeal chordoma is located right to the midline with infiltration of the pelvis and the gluteal muscles (white rectangles). Corresponding apparent diffusion coefficient (ADC) maps derived from diffusion-weighted imaging of the tumor area are shown in the top right corner of each panel. Compared to baseline 2, a reduction of tumor bulk, especially the intrapelvic component, and increased necrosis, as indicated by new areas with lack of contrast enhancement, were seen. An increase in ADC from 1030 mm²s⁻¹ to 1352 mm²s⁻¹ between both time points indicates a reduction in cellularity (yellow arrows)