A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer

Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their melanoma reveals that 16% of somatic variants localize to sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-associated mutagenesis. Centromere kinetochore binding domains emerge as focal sites of chromosome arm aneuploidy breakpoints and somatic genetic variation, features we further demonstrate are also present in non-cancerous tissues. By contrast, extensive epigenetic remodeling of kinetochore binding domains appears specific to oncogenesis. Single-molecule telomere analyses reconstruct the cycle of telomere erosion and telomerase-mediated extension during tumor evolution, while haplotype-resolved chromatin maps reveal widespread somatic epimutations impacting regulatory elements. Together, these findings define previously inaccessible dimensions of somatic variation and establish a framework for telomere-to-telomere studies of human mosaicism.