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Modeling double strand break susceptibility to interrogate structural variation in cancer.

Authors :
Ballinger TJ
Bouwman BAM
Mirzazadeh R
Garnerone S
Crosetto N
Semple CA
Source :
Genome biology [Genome Biol] 2019 Feb 08; Vol. 20 (1), pp. 28. Date of Electronic Publication: 2019 Feb 08.
Publication Year :
2019

Abstract

Background: Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge from errors in the repair processes following DNA double strand breaks (DSBs).<br />Results: We used experimentally quantified DSB frequencies in cell lines with matched chromatin and sequence features to derive the first quantitative genome-wide models of DSB susceptibility. These models are accurate and provide novel insights into the mutational mechanisms generating DSBs. Models trained in one cell type can be successfully applied to others, but a substantial proportion of DSBs appear to reflect cell type-specific processes. Using model predictions as a proxy for susceptibility to DSBs in tumors, many SV-enriched regions appear to be poorly explained by selectively neutral mutational bias alone. A substantial number of these regions show unexpectedly high SV breakpoint frequencies given their predicted susceptibility to mutation and are therefore credible targets of positive selection in tumors. These putatively positively selected SV hotspots are enriched for genes previously shown to be oncogenic. In contrast, several hundred regions across the genome show unexpectedly low levels of SVs, given their relatively high susceptibility to mutation. These novel coldspot regions appear to be subject to purifying selection in tumors and are enriched for active promoters and enhancers.<br />Conclusions: We conclude that models of DSB susceptibility offer a rigorous approach to the inference of SVs putatively subject to selection in tumors.

Details

Language :
English
ISSN :
1474-760X
Volume :
20
Issue :
1
Database :
MEDLINE
Journal :
Genome biology
Publication Type :
Academic Journal
Accession number :
30736820
Full Text :
https://doi.org/10.1186/s13059-019-1635-1