Nik-Zainal, S. | bioRxiv Science

bioRxiv2018

Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Global loss of DNA methylation and CpG island (CGI) hypermethylation are regarded as key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which can extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. Using whole genome bisulfite sequencing (WGBS) of breast cancers, we comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of variation in DNA methylation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). However, significant repression effects on cancer-genes are negligible as tumor suppressor genes are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin of different cancers and may represent tissue-specific silent regions of the genome, which tolerate instability at the epigenetic, transcriptomic and genetic level.

cancer biology↗

bioRxiv2017

Non-canonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis

Somatic mutations show variation in density across cancer genomes. Previous studies have shown that chromatin organization and replication time domains are correlated with and thus predictive of this variation 1,2,3,4,5. Here, we analyse 1,809 whole-genome sequences from nine cancer types 6,7,8 to show that a subset of repetitive DNA sequences called non-B motifs that predict non-canonical secondary structure formation 9,10,11,12 can independently account for variation in mutation density. However, combined with epigenetic factors and replication timing, the variance explained can be improved to 43-76%. Intriguingly, ~2-fold mutation enrichment is observed directly within non-B motifs, is focused on exposed structural components, and is dependent on physical properties that are optimal for secondary structure formation. Therefore, there is mounting evidence that secondary structures arising from non-B motifs are not simply associated with increased mutation density, they are possibly causally implicated. Our results suggest that they are determinants of mutagenesis and increase the likelihood of recurrent mutations in the genome 13,6. This analysis calls for caution in the interpretation of recurrent mutations and highlights the importance of taking non-B motifs, that can simply be inferred from the reference sequence, into consideration in background models of mutability henceforth.

genomics↗