Fig. 2. NF2/22q loss correlates with detectable ctDNA and late progression in MPM.

A Left. Kaplan-Meier plot showing the relative survival of patients with detectable, clonal driver mutations present in the circulating tumour DNA (ctDNA). Overall survival was significantly lower for patients positive for ctDNA (Two-sided Log-rank test p = 0.020; hazard ratio 5.20; 95% confidence intervals: 1.12, 24.09). Right. Column chart showing that patients who had detectable ctDNA (black column) were more likely to have a NF2 mutant tumour (two-sided Fisher’s exact test p = 0.015; Odds ratio is infinite because all ctDNA-positive tumours were NF2 mutants; 95% confidence intervals: 1.27, infinite). n = 11 patients. B Longitudinal sampling of tissue from a patient taken at the time of radical pleurectomy decortication (this patient was not enroled into MEDUSA). Array based SCNA analysis was conducted showing subclonal loss of 22q at first progression with a higher SCNA burden, ~12 years following surgery. Subsequent progression was associated with drug resistance (CT scan top right). The squares at the base show copy number losses in blue and gains/amplifications in red. The time from final progression to death was 29 days. C Stacked mountain plot summarising clonal versus subclonal losses (above, green) compared with gains (orange/truncal, red/branch) below. This figure shows the relative frequency (y axis) of copy number losses compared with gains along the whole-exome (x axis) averaged across the cohort of patients. D Nuclear YAP expression in a cell line derived from patient MED85 harbouring deletion of NF2, compared with wild-type NF2 (MED96) showing non-nuclear YAP expression (right panel). Confocal images: FV1000 (Olympus), ×60 objective, ×4 zoomed scale bars = 10 μm. E Heatmap summarising arm level losses in the MEDUSA22 cohort by chromosome (left column). The clonal (blue) versus subclonal (grey) frequency of arm level losses per chromosome are shown in the histogram on the right.