Functional chromatin features are associated with structural mutations in cancer

BMC Genomics

Jeffrey H Chuang¹  Edison T Liu²  Axel M Hillmer⁴  Hyunsoo Kim¹  Koichiro Inaki¹  Beryl Royer-Bertrand³  Krzysztof R Grzeda¹ 

[1] The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA;The Jackson Laboratory, Bar Harbor, ME, 04609, USA;Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland;Genome Technology and Biology, Genome Institute of Singapore, Singapore 138672, Singapore

关键词: Cancer;    Structural mutations;    Chromatin state;    Protein binding;   

Others  :  1091396
DOI  :  10.1186/1471-2164-15-1013

 received in 2014-06-30, accepted in 2014-11-12,  发布年份 2014

【 摘 要 】

Background

Structural mutations (SMs) play a major role in cancer development. In some cancers, such as breast and ovarian, DNA double-strand breaks (DSBs) occur more frequently in transcribed regions, while in other cancer types such as prostate, there is a consistent depletion of breakpoints in transcribed regions. Despite such regularity, little is understood about the mechanisms driving these effects. A few works have suggested that protein binding may be relevant, e.g. in studies of androgen receptor binding and active chromatin in specific cell types. We hypothesized that this behavior might be general, i.e. that correlation between protein-DNA binding (and open chromatin) and breakpoint locations is common across divergent cancers.

Results

We investigated this hypothesis by comprehensively analyzing the relationship among 457 ENCODE protein binding ChIP-seq experiments, 125 DnaseI and 24 FAIRE experiments, and 14,600 SMs from 8 diverse cancer datasets covering 147 samples. In most cancers, including breast and ovarian, we found enrichment of protein binding and open chromatin in the vicinity of SM breakpoints at distances up to 200 kb. Furthermore, for all cancer types we observed an enhanced enrichment in regions distant from genes when compared to regions proximal to genes, suggesting that the SM-induction mechanism is independent from the bias of DSBs to occur near transcribed regions. We also observed a stronger effect for sites with more than one protein bound.

Conclusions

Protein binding and open chromatin state are associated with nearby SM breakpoints in many cancer datasets. These observations suggest a consistent mechanism underlying SM locations across different cancers.

【 授权许可】

   
2014 Grzeda et al.; licensee BioMed Central Ltd.

【 图 表 】

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