Nuclear topology modulates the mutational landscapes of cancer genomes

Nuclear organization of genomic DNA affects DNA damage and repair processes, and yet its impact on mutational landscapes in cancer genomes remains unclear. Here we analyzed genome-wide somatic mutations from 366 samples of 6 cancer types. We found that lamina-associated regions, which are typically localized at the nuclear periphery, displayed higher somatic mutation frequencies compared to the inter-lamina regions at the nuclear core. This effect remained even after adjusting for features such as GC%, chromatin, and replication timing. Furthermore, mutational signatures differed between the nuclear core and periphery, indicating differences in the patterns of DNA damage and/or DNA repair processes. For instance, smoking and UV-related signatures were more enriched in the nuclear periphery. Substitutions at certain motifs were also more common in the nuclear periphery. Taken together, we found that the nuclear architecture influences mutational landscapes in cancer genomes beyond the effects already captured by chromatin and replication timing.