Somatic mutation footprinting reveals a unique tetra-nucleotide signature associated with intron-exon boundaries in lung cancer
- Author(s)
- Wormald, S; Lerch, A; Mouradov, D; O'Connor, L;
- Journal Title
- Carcinogenesis
- Publication Type
- Journal Article in press
- Abstract
- Cigarette smoke comprises a large number of carcinogenic substances that can increase DNA mutation load in epithelial cells of the mouth, throat and lungs. While a strong C:A substitution preference is abundant in tobacco-related cancer genomes, detection of complex or less abundant somatic mutation signatures may be confounded by the heterogeneity of carcinogens present in smoke. Tri-nucleotide signatures are defined for a variety of somatic mutation processes, yet the extent to which this configuration optimally defines and discriminates between mutational processes is not clear.Here, we describe a method that determines whether tri-nucleotide patterns do a good job at encapsulating a mutation signature, or whether they mask underlying heterogeneity that alternative pattern structures would better define. The approach works by mapping the dependency of tri-nucleotide signatures in relation to sequence context to establish a "footprint" of context dependency.Applying this technique to smoke-associated cancers, we show that a robust tetra-nucleotide substitution is prevalent in 17% of lung squamous cell carcinoma genomes. The signature is dominated by the substitution CT(C:A)G, and is strongly associated with gene expression level and intron-exon junctions. Intriguingly, its distribution across the genome is biased towards 5' splice junctions, suggesting a novel mechanism of mutation.
- Publisher
- Oxford Academic
- Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- 29206898
- Publisher's Version
- https://doi.org/10.1093/carcin/bgx133
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-01-15 09:30:02
Last Modified: 2018-01-15 09:43:09