Topographical signatures of single-base substitutions in cancer

A genome-resolved atlas of mutational signatures across 15 cancer types, organised by their topographic archetypesTopo-5mcMutagenesis at methylated CpG sites in repressive chromatin, driven by polymerase errors, spontaneous deamination, or active demethylation at 5-methylcytosine.Topo-RepReplication-associated mutagenesis enriched in early-replicating regions, including signatures of homologous recombination deficiency.Topo-TrTranscription-associated mutagenesis in active chromatin, shaped by transcription-coupled repair and translesion synthesis.Topo-RepAPOBECAPOBEC mutagenesis with a replication-associated profile, enriched in early-replicating regions and in tumors under replication stress.Topo-CanAPOBECCanonical APOBEC activity biased toward late-replicating regions; predominantly SBS2.Topo-StressDDamage-associated mutagenesis under replication stress, shifted toward earlier replication timing relative to its canonical counterparts.Topo-CanD ICanonical damage mutagenesis enriched in late-replicating regions with broad heterochromatin association.Topo-CanD IIDamage mutagenesis confined to constitutive heterochromatin; the most late-replicating regime.topographic archetypes — conserved patterns of how mutational processes are distributed across the genome, shaped by replication timing and chromatin state — explore all signatures.

208 signatures across 15 cancer types, classified into 8 topotypes by genome-wide mutation rate profiles.