RT Journal Article
SR Electronic
T1 CpG methylation accounts for genome-wide C>T mutation variation and cancer driver formation across cancer types
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 106872
DO 10.1101/106872
A1 Rebecca C. Poulos
A1 Jake Olivier
A1 Jason W. H. Wong
YR 2017
UL http://biorxiv.org/content/early/2017/02/08/106872.abstract
AB Cytosine methylation (5mC) is vital for cellular function, and yet 5mC sites are also commonly mutated in the genome. In this study, we analyse the genomes of over 900 cancer samples, together with tissue type-specific methylation and replication timing data. We describe a strong mutation-methylation association in colorectal cancers with microsatellite instability (MSI) or with Polymerase epsilon (POLE) exonuclease domain mutation. We describe a potential role for mismatch repair in the correction of mismatches resulting from deamination of 5mC, and propose a mutator phenotype to exist in POLE-mutant cancers specifically at 5mC sites. We also associate POLE-mutant hotspot coding mutations in APC and TP53 with CpG methylation. Analysing mutations across additional cancer types, we identify nucleotide excision repair- and AID/APOBEC-induced processes to underlie differential mutation-methylation associations in certain cancer subtypes. This study reveals differential associations vital for accurately mapping regional variation in mutation density and pinpointing driver mutations in cancer.