Extended Data Fig. 2: AR gene and enhancer amplification mechanisms and amplicon structure in cfDNA and metastatic tissue.

(a) AR-neighbourhood copy number structure in same-day patient-matched cfDNA and metastatic tissue. Upper and lower plots display absolute copy number (i.e. corrected for tumour content) and uncorrected coverage log ratios, respectively. In this patient, the tissue sample shows a focal amplification of the AR enhancer region and a broad copy gain of the entire locus, whereas the cfDNA sample shows a more complex pattern of apparent nested copy gains. Despite these contrasting structures, the overall AR enhancer and gene body copy numbers are relatively similar (considering that the range of AR gene body absolute copy number across all samples was 1-91). (b) Absolute copy number across the AR gene and enhancer neighbourhood for three cfDNA samples and one tissue sample. Pileup of all per-sample structural arrangements shown below (indicating dominant mechanisms of copy amplification). Note evidence of local enhancer copy loss in patients, suggestive of enhanced cfDNA degradation owing to nucleosome depletion³⁸. (c) Average copy number change at the AR locus across serial ctDNA collected during systemic treatment with AR signalling inhibitors. Structural variant breakpoints and tandem duplication events from all cfDNA and tissue samples (regardless of time point) are shown below, illustrating a convergence toward amplification of the AR gene and enhancer.