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Somatic mutation footprinting reveals a unique tetranucleotide signature associated with intron-exon boundaries in lung cancer

Wormald, Samuel and Lerch, Anita and Mouradov, Dmitri and O'Connor, Liam. (2018) Somatic mutation footprinting reveals a unique tetranucleotide signature associated with intron-exon boundaries in lung cancer. Carcinogenesis, 39 (2). pp. 225-231.

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Official URL: https://edoc.unibas.ch/60971/

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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. Trinucleotide 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 trinucleotide 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 trinucleotide 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 tetranucleotide 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Diagnostics (Felger)
UniBasel Contributors:Lerch, Anita AL
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
ISSN:0143-3334
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:27 Jun 2018 09:17
Deposited On:27 Jun 2018 09:17

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