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

Abstract

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 mutations1, posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape1-5. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific6,7. 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.

Roadmap for regulation

“…The authors found that these variants are often located in or near enhancers [2][3][4][5][6][7][8][9] , and encompassing embryonic and adult tissues, from healthy individuals and those with disease. a, Many of the adult tissues investigated were broken down by cell type or region -blood into several types of immune cell, for instance, and the brain into regions including the hippocampus and dorsolateral prefrontal cortex.…”

“…For example, flanking sequences might have a topological role affecting chromatin packaging and, consequently, DNA accessibility. Polak et al 8 (page 360) investigated the distribution of cancer-associated genetic mutations in a set of diverse cancers, and correlated them with cell-type-specific epi genomic features. They found that the mutation profile of each cancer could often be predicted from the epigenomic signature of the cell type from which that cancer was most likely to have originated.…”

“…For instance, three studies investigate the histone modifications associated with disease [6][7][8] . Focusing on normal development, Tsankov et al 4 and Ziller et al 5 have mapped histone modifications that occur during the differentiation of embryonic cells (specifically, H3K4me1, H3K4me3, H3K27ac and H3K37me modifications), alongside patterns of transcription-factor binding and DNA methylation.…”

Comment l’approche génomique aide à comprendre le processus d’initiation de la réplication

“…L'absence d'origines bien localisées serait ainsi une des causes de la fragilité de ces régions du génome [10][11][12]. Les délétions récurrentes et les régions où s'accumulent les mutations ponctuelles dans les cancers sont, pour la plupart, localisées dans des régions répliquées en fin de phase S [10,[13][14][15]. Inversement, les régions répliquées en début de phase S contiennent des régions fréquemment amplifiées [13][14][15].…”

“…Les délétions récurrentes et les régions où s'accumulent les mutations ponctuelles dans les cancers sont, pour la plupart, localisées dans des régions répliquées en fin de phase S [10,[13][14][15]. Inversement, les régions répliquées en début de phase S contiennent des régions fréquemment amplifiées [13][14][15]. Il existerait donc une relation, peutêtre causale, entre la densité en origines de réplication d'une région du génome et la nature des réarrangements chromosomiques que l'on observe dans les cancers.…”