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Abstract
Methylated cytosines (5mCs) are frequently mutated in the genome. However, no studies have yet comprehensively analysed mutation–methylation associations across cancer types. Here we analyse 916 cancer genomes, together with tissue type-specific methylation and replication timing data. We describe a strong mutation–methylation association across colorectal cancer subtypes, most interestingly in samples with microsatellite instability (MSI) or Polymerase epsilon (POLE) exonuclease domain mutations. By analysing genomic regions with differential mismatch repair (MMR) efficiency, we suggest a possible role for MMR in the correction of 5mC deamination events, potentially accounting for the high rate of 5mC mutation accumulation in MSI tumours. Additionally, we propose that mutant POLE asserts a mutator phenotype specifically at 5mCs, and we find coding mutation hotspots in POLE-mutant cancers at highly-methylated CpGs in the tumour-suppressor genes APC and TP53. Finally, using multivariable regression models, we demonstrate that different cancers exhibit distinct mutation–methylation associations, with DNA repair influencing such associations in certain cancer genomes. Taken together, we find differential associations with methylation that are vital for accurately predicting expected mutation loads across cancer types. Our findings reveal links between methylation and common mutation and repair processes, with these mechanisms defining a key part of the mutational landscape of cancer genomes.
Highlights
Cancer develops as somatic mutations accumulate in cells, with certain driver mutations conferring a growth advantage to a sub-population (Nowell, 1976)
Recent studies investigating the accumulation of somatic mutations in cancer have shown that mutations in many cancer types increase at promoters due to inhibition of nucleotide excision repair (NER) at transcription factor bindings sites (Perera et al, 2016; Sabarinathan et al, 2016)
Using tissue-specific methylation data, we describe a strong association between C>T mutations and methylation at CpG dinucleotides in many cancer types, driving patterns of mutation formation throughout the genome
Summary
Cancer develops as somatic mutations accumulate in cells, with certain driver mutations conferring a growth advantage to a sub-population (Nowell, 1976). Mutations develop primarily from exposure to exogenous mutagens such as ultraviolet (UV) light or cigarette smoke, while in other cancer types, most mutations accumulate after a cell develops defective replication or repair mechanisms (Vogelstein et al, 2013). Methylation has important functions within a cell, influencing development (Smith and Meissner, 2013), gene expression and silencing (Doerfler, 2006), as well as being implicated in carcinogenesis (Jones and Baylin, 2002)
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