Extended Data Fig. 4. Structural variations, complex genomic rearrangements (CGRs) and extrachromosomal DNAs (ecDNAs) amplicons, and mutations.
(a) Spectra of rearrangement signatures (RSs) among early or late structural variations (SVs) in RAM cases (n = 5 cases; n = 5 sites). (b) Spectra of RSs among early, intermediate, or late SVs in a clinical MAPKi-treated, patient-matched pre-and-post melanoma cohort (n = 10 patients; n = 10 baseline tumors; n = 17 disease progression or DP tumors). (c) Distribution of double-stranded DNA break (DSB) repair processes (non-homologous end-joining or NHEJ, alternative NHEJ or alt-NHEJ, homologous recombination repair or HRR) inferred by breakpoint-junctional sequence analysis of early or late SVs of RAM cases in (a). (d) Distribution of DSB repair processes inferred by breakpoint-junctional sequence analysis of early, intermediate, or late SVs of the cohort in (b). For cases with multiple DPs, average values are presented. (e) SV plot indicating CGR harboring BRAF in a lung metastasis. Horizontal black and red lines indicate respectively genomic segments with similar copy numbers and genes. Short vertical lines and arcs indicate discordant read pairs linking two amplicons via a structural variant junction. Long vertical lines indicate break ends that map from amplicon into low-complexity regions which cannot be traced further. Each line/arc representing discordant reads is colored based on differences from expected distance or orientation. (f) Chromosomal distribution of ecDNAs and CGRs in RAMs (n = 22; one remained sensitive to treatment; 21 with acquired MAPKi-resistance) across organs, deceased patients, and treatment histories. Circles and Xs represent ecDNAs and CGRs, respectively. The size of circles or Xs indicates the number of copy number variant segments (reference sizes shown). (g) Distribution of mutant (variant) allele frequencies in early, intermediate, or late mutations for RAM12.01 and RAM14006.