Fig. 3: Whole-genomic landscape of therapy-resistant cutaneous melanoma.
a, TMBs based on somatic IDs, SNVs and SVs across 22 tumors (eight cases), organs and treatment histories. b,c, Spectra of RSs among all SVs (b) or early, intermediate and late SVs (c). Tumors analyzed in c derived from phylogenetic analysis of two RAM cases with multiple tumors. d, Distribution of DNA DSB repair processes (NHEJ, alternative NHEJ and HRR) inferred by breakpoint junctional sequence analysis of early, intermediate and late SVs of RAM cases in c. Homologous sequence lengths at breakpoints of 0–1 bp, 2–6 bp or >6 bp infer NHEJ, alternative NHEJ and HRR, respectively. e, SVs across genomic locations and affected genes. Outer layer, chromosome locations; second layer, large (>1 Mb) duplications (red); third layer, large deletions (blue); inner layer, a combination of both duplications and deletions (yellow); frequencies of occurrence increase from inner to outer circles. Inside the circles, recurrent (≥4 of 21 resistant RAM tumors) intra-chromosomal or inter-chromosomal translocations. f, Pathways enriched in genes overlapping somatic SVs detected in ≥50% (11/21) of RAM tumors (one-sided Fisher’s exact test, adjusted by FDR). g, As in e, except sub-analyses based on treatment histories and recurrent translocation in ≥3 tumors in each treatment history category. h, SV plot indicating extrachromosomal DNA amplicon harboring BRAF in a brain metastasis. Horizontal black and red lines indicate, respectively, genomic segments with similar copy numbers and genes. Each line/arc representing discordant reads is colored based on differences from expected distance or orientation. i, Spectra of SBS and ID signatures based on WGS across 22 tumors (eight cases), organs and treatment histories. j, Proportions of SBS mutational signatures associated with defective MMR, per treatment history (n = 22 tumors). Central line of each box, median; top and bottom edges of each box, first and third quartiles; whiskers extend 1.5× the interquartile range beyond box edges. k, As in i, except for early, intermediate and late SBS mutations in two RAM cases with phylogenetic data.
