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

Abstract

An analysis of cell-type-specific epigenomic features reveals a relationship between epigenomic and mutational profiles; chromatin characteristics can explain a large proportion of mutational variance in cancer genomes and the mutational distribution can identify the probable cell type from which a given cancer originated from. Genomic studies have shown that different cancer types vary substantially in the local density and types of somatic mutations. This has been explained not only by differences in DNA sequence but also by other features including epigenetic organization. Shamil Sunyaev and colleague now compare mutation densities to detailed epigenetic profiles of different cell types and tissues. They demonstrate that epigenomic features of a given cell type or tissue in which a cancer arises are much stronger determinants of mutational profiles than other properties. Conversely, the findings make it possible to deduce information on the possible tissue-of-origin of a tumour based on its mutational landscape. Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations1, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape1,2,3,4,5. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific6,7. We investigated the distribution of mutations in multiple independent 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. 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 matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.