Cell-of-origin chromatin organization shapes the mutational landscape of cancer

Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the genome. Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations(1), posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape(1-5). However, both somatic mutagenesis and epigenomic features are highly cell-type-specific(6,7). We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. Overwhelmingly, the best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of cognate cancer cell lines. We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.