Cancer mutational processes vary in their association with replication timing and chromatin accessibility

Abstract

BackgroundCancer somatic mutations are the product of multiple mutational and repair processes, which are tightly associated with DNA replication. Distinctive patterns of somatic mutations accumulation in tumors, termed mutational signatures, are indicative of processes the tumors underwent. While tumor mutational load is correlated with late replicating regions and spatial genome organization, much is unknown about the association of many different mutational processes and replication timing, and the interplay with chromatin structure remains an open question.MethodsWe systematically analyzed the mutational landscape of 2,787 WGS tumors from 32 different tumor types separately for early and late replicating regions. We used sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences between early and late replicating regions. Moreover, we expanded the signature analyses to doublet base substitutions and small insertions and deletions by developing an artificial genomes-based approach to account for sequence differences between various genomic regions.ResultsWe revealed the replication timing (RT) association of single base, doublet base and small insertions and deletions mutational signatures. The association is signature specific: some are associated with early or late replication (such as UV-exposure signatures SBS7b and SBS7a, respectively) and others have no association. Most associations exist even after normalizing for genome accessibility. We further developed a focused mutational signature identification approach, which uses RT information to improve signature identification, and found that SBS16, which is biased towards early replication, is strongly associated with better survival rates in liver cancer.ConclusionsOur comprehensive analyses enabled a more robust classification of RT association of single base, doublet base and indels signatures. By doing so, we demonstrated a variation in the association with RT, as many mutational processes biased towards either early or late replication timing, and others have an equal RT distribution. These associations were independent from chromatin accessibility in most cases. This work highlights that restricting signatures analyses to concise genomic regions improves identification of signatures, such as SBS16, and demonstrates its clinically relevance as a predictor of improved survival of liver cancer patients.

Multifactorial heterogeneity of the human mutation landscape related to DNA replication dynamics

“…To prevent signature overfitting, we selected a subset of signatures for each cell type based on biologically expected mutational pathways. In CLL, SBS 1, 5, 9 and 40 are established as the predominant mutational signatures 1,28,33,45 . SBS 1, 5, and 40, are clock-like signatures – highly ubiquitous signatures of unknown etiology that increase in abundance with age 1,46 .…”

“…Some mutational processes are shared (e.g., those manifesting as single base substitution (SBS) signatures 1, 5, and 40), and others are more specific to subsets of cell or cancer types (e.g., MMR deficiency). Previous studies showed that different mutational processes – and their resulting mutational signatures – have differential relationships to replication timing 10,12,15,27,28 . For example, SBS signatures 1, 8, 9, and 17 were shown to be enriched in late replicating regions of the genome, while SBS 5, 21, 40, and 44 showed either bias to early replication or no bias at all.…”

“…Previous studies that established how mutational processes relate to DNA replication have assumed that any given process relates to replication timing and strand bias in a constant way. However, it is becoming increasingly clear that mutational processes may be heterogeneous not only in their quantity across cell/cancer types, but also in their relation to replication dynamics across cell types 1,27,28 . This complexity has led to conflicting conclusions among different studies.…”

“…For example, signature SBS 1 (caused by spontaneous deamination of 5-methylcytosine to thymine) has been reported by different studies to be biased toward early replication, late replication, or neither 10,15,28 . Similarly inconsistent conclusions have been proposed for SBS 5, 40, and others 10,15,28 . These conflicting results could be reconciled if additional, orthogonal factors that vary within and between cell types affect the relationship of mutational processes to DNA replication timing.…”

“…This complexity has led to conflicting conclusions among different studies. For example, signature SBS 1 (caused by spontaneous deamination of 5-methylcytosine to thymine) has been reported by different studies to be biased toward early replication, late replication, or neither 10,15,28 . Similarly inconsistent conclusions have been proposed for SBS 5, 40, and others 10,15,28 .…”