Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers

Abstract

AbstractSomatic mutations in human cells have a highly heterogeneous genomic distribution, with increased burden in late-replication time (RT), heterochromatic domains of chromosomes. This regional mutation density (RMD) landscape is known to vary between cancer types, in association with tissue-specific RT or chromatin organization. Here, we hypothesized that regional mutation rates additionally vary between individual tumors in a manner independent of cell type, and that recurrent alterations in DNA replication programs and/or chromatin organization may underlie this. Here, we identified various RMD signatures that describe a global genome-wide mutation redistribution across many megabase-sized domains in >4000 tumors. We identified two novel global RMD signatures of somatic mutation landscapes that were universally observed across various cancer types. First, we identified a mutation rate redistribution preferentially affecting facultative heterochromatin, Polycomb-marked domains, and enriched in subtelomeric regions. This RMD signature strongly reflects regional plasticity in DNA replication time and in heterochromatin domains observed across tumors and cultured cells, which was linked with a stem-like phenotype and a higher expression of cell cycle genes. Consistently, occurrence of this global mutation pattern in cancers is associated with altered cell cycle control via loss of activity of theRB1tumor suppressor gene. Second, we identified another independant global RMD signature associated with loss-of-function of theTP53pathway, mainly affecting the redistribution of mutation rates away from late RT regions. The local mutation supply towards 26%-75% cancer driver genes is altered in the tumors affected by the global RMD signatures detected herein, including additionally a known pattern of a general loss of mutation rate heterogeneity due to DNA repair failures that we quantify. Our study highlights that somatic mutation rates at the domain scale are variable across tumors in a manner associated with loss of cell cycle control viaRB1orTP53, which may trigger the local remodeling of chromatin state and the RT program in cancers.