Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair

Carcinogenesis and neoplastic progression are mediated by the accumulation of somatic mutations. Here we report that the local density of somatic mutations in cancer genomes is highly reduced specifically in accessible regulatory DNA defined by DNase I hypersensitive sites. This reduction is independent of any known factors influencing somatic mutation density and is observed in diverse cancer types, suggesting a general mechanism. By analyzing individual cancer genomes1, we show that the reduced local mutation density within regulatory DNA is linked to intact global genome repair machinery, with nearly complete abrogation of the hypomutation phenomenon in individual cancers that possess mutations in multiple nucleotide excision repair components. Together, our results connect chromatin structure, gene regulation and cancer-associated somatic mutation. Somatic mutations are a major contributor to cancer development and progression. In cancer cells, the density of somatic mutations is highly heterogeneous along the genome2,3. However, mechanisms governing the genomic distribution of somatic mutations are poorly understood. Recently, cancer genomics efforts have accumulated data on somatic mutations in tumors4, revealing that the relative density of somatic mutations in protein coding genes #Correspondence