title: 5-hydroxymethylcytosine marks regions with reduced mutation frequency in human DNA.
abstract: CpG dinucleotides are the main mutational hot-spot in most cancers. The characteristic elevated C>T mutation rate in CpG sites has been related to 5-methylcytosine (5mC), an epigenetically modified base which resides in CpGs and plays a role in transcription silencing. In brain nearly a third of 5mCs have recently been found to exist in the form of 5-hydroxymethylcytosine (5hmC), yet the effect of 5hmC on mutational processes is still poorly understood. Here we show that 5hmC is associated with an up to 53% decrease in the frequency of C>T mutations in a CpG context compared to 5mC. Tissue specific 5hmC patterns in brain, kidney and blood correlate with lower regional CpG>T mutation frequency in cancers originating in the respective tissues. Together our data reveal global and opposing effects of the two most common cytosine modifications on the frequency of cancer causing somatic mutations in different cell types.
authors.affiliation: Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom.
authors.forename: Marketa
authors.initials: M
authors.lastname: Tomkova
authors.affiliation: Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: McClellan
authors.affiliation: Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom.
authors.forename: Skirmantas
authors.initials: S
authors.lastname: Kriaucionis
authors.affiliation: Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom.
authors.forename: Benjamin
authors.identifier: 0000-0002-8892-5133
authors.initials: B
authors.lastname: Schuster-Boeckler
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059645:Mutation Rate; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D000073359:Exome Sequencing
chemical_list: D004273:DNA, Neoplasm; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine
keywords: DNA methylation; cancer biology; cancer genomics; computational biology; human; hydroxymethylcytosine; somatic mutation; systems biology