Functional chromatin features are associated with structural mutations in cancer.

Authors

Krzysztof R. Grzeda, The Jackson LaboratoryFollow
Beryl Royer-Bertrand
Koichiro Inaki
Hyunsoo Kim, The Jackson LaboratoryFollow
Axel M Hillmer
Edison T. Liu, The Jackson LaboratoryFollow
Jeffrey Chuang, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

11-23-2014

JAX Source

BMC Genomics 2014 Nov 23; 15:1013.

Volume

15

First Page

1013

Last Page

1013

ISSN

1471-2164

PMID

25417144

Abstract

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.

BMC Genomics 2014 Nov 23; 15:1013.

Recommended Citation

Grzeda KR, Royer-Bertrand B, Inaki K, Kim H, Hillmer A, Liu ET, Chuang J. Functional chromatin features are associated with structural mutations in cancer. BMC Genomics 2014 Nov 23; 15:1013.