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Nucleic Acids Res. 2017 Jul 27;45(13):7786-7795. doi: 10.1093/nar/gkx463.

The interaction between cytosine methylation and processes of DNA replication and repair shape the mutational landscape of cancer genomes.

Author information

1
Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Sydney, NSW 2052, Australia.
2
School of Mathematics and Statistics, The Red Centre, UNSW Sydney, NSW 2052, Australia.

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.

PMID:
28531315
PMCID:
PMC5737810
DOI:
10.1093/nar/gkx463
[Indexed for MEDLINE]
Free PMC Article

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