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.
Highlights
Cancer genomics projects have revealed that the distribution of somatic mutations across the genome is not uniform (Lawrence et al, 2013)
Based on a DNA sequencing data from five brain cancer types encompassing 665 patients, we show that the dominant mutational signature in brain cancers is CpG>T, which is modulated by the modification state of cytosine
We find that the ratio of 5hmC to 5mC in 100 kb genomic intervals correlates with CpG>T mutation frequency even after accounting for confounding factors like gene density or CpG islands
Summary
Cancer genomics projects have revealed that the distribution of somatic mutations across the genome is not uniform (Lawrence et al, 2013). Highly transcribed regions generally exhibit lower mutation frequencies due to the influence of transcription-coupled repair (Lawrence et al, 2013). The most frequent mutational signature found in the majority of cancers is C to T transition in a CpG dinucleotide context (CpG>T) (Alexandrov et al, 2013; Lawrence et al, 2013). This relates to the fact that cytosines in CpG dinucleotides are frequently methylated to form 5-methylcytosine (5mC). In the germline of vertebrates, this likely facilitated a general depletion of CpGs outside of CpG islands which are largely unmethylated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
