Variability in Chromatin Architecture and Associated DNA Repair at Genomic Positions Containing Somatic Mutations.

Byungho Lim,Jihyeob Mun,Yong Sung Kim,Seon-Young Kim

doi:10.1158/0008-5472.can-16-3033

Abstract

Dynamic chromatin structures result in differential chemical reactivity to mutational processes throughout the genome. To identify chromatin features responsible for mutagenesis, we compared chromatin architecture around single-nucleotide variants (SNV), insertion/deletions (indels), and their context-matched, nonmutated positions. We found epigenetic differences between genomic regions containing missense SNVs and those containing frameshift indels across multiple cancer types. Levels of active histone marks were higher around frameshift indels than around missense SNV, whereas repressive histone marks exhibited the reverse trend. Accumulation of repressive histone marks and nucleosomes distinguished mutated positions (both SNV and indels) from the context-matched, nonmutated positions, whereas active marks were associated with substitution- and cancer type-specific mutagenesis. We also explained mutagenesis based on genome maintenance mechanisms, including nucleotide excision repair (NER), mismatch repair (MMR), and DNA polymerase epsilon (POLE). Regional NER variation correlated strongly with chromatin features; NER machineries exhibited shifted or depleted binding around SNV, resulting in decreased NER at mutation positions, especially at sites of recurrent mutations. MMR-deficient tumors selectively acquired SNV in regions with high active histone marks, especially H3K36me3, whereas POLE-deficient tumors selectively acquired indels and SNV in regions with low active histone marks. These findings demonstrate the importance of fine-scaled chromatin structures and associated DNA repair mechanisms in mutagenesis. Cancer Res; 77(11); 2822-33. ©2017 AACR.

Highlights

Somatic mutations are the first-line genetic drivers of malignant transformation of normal tissues
To identify the chromatin architectures at genomic positions containing somatic mutations, we curated somatic single-nucleotide variants (SNV) and small indels that were detected from whole exomes of 12 cancer types and whole genomes of stomach adenocarcinoma [23] and skin cutaneous melanoma (Supplementary Table S1)
When nucleosome occupancy was examined with regard to the 12 substitution types of SNVs, nucleosomes were consistently accumulated at mutation positions for all 12 substitution types (Supplementary Fig. S3)

Summary

Introduction

Somatic mutations are the first-line genetic drivers of malignant transformation of normal tissues. Despite the importance of mutation, the mechanism by which mutations are acquired is largely unknown. Mutations have been supposed to arise via the interplay of random events. Recent studies have begun to reveal that mutations are nonrandomly distributed across the human genome, in relation to chromatin organization [1,2,3], the timing of DNA replication [4, 5], and DNA repair [6,7,8,9,10]. Chromatin is a highly ordered macromolecular structure consisting of dynamic interactions between DNA sequences, RNAs, and proteins. The multifaceted chromatin structure may cause genomic position–specific chemical reactivity when muta-

Methods

Results

Conclusion