Nuclear topology modulates the mutational landscapes of cancer genomes

Nuclear organization of genomic DNA affects processes of DNA damage and repair, yet its effects on mutational landscapes in cancer genomes remain unclear. Here we analyzed genome-wide somatic mutations from 366 samples of six cancer types. We found that lamina-associated regions, which are typically localized at the nuclear periphery, displayed higher somatic mutation frequencies than did the interlamina regions at the nuclear core. This effect was observed even after adjustment for features such as GC percentage, chromatin, and replication timing. Furthermore, mutational signatures differed between the nuclear core and periphery, thus indicating differences in the patterns of DNA-damage or DNA-repair processes. For instance, smoking and UV-related signatures, as well as substitutions at certain motifs, were more enriched in the nuclear periphery. Thus, the nuclear architecture may influence mutational landscapes in cancer genomes beyond the previously described effects of chromatin structure and replication timing.