Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer

Matteo D'antonio, Donate Weghorn, Agnieszka D'antonio-Chronowska, Florence Coulet, Katrina M. Olson, Christopher Deboever, Frauke Drees, Angelo Arias, Hakan Alakus, Andrea Richardson, Richard B. Schwab, Emma K. Farley, Shamil R. Sunyaev, Kelly A. Frazer

Research output: Contribution to journalArticle

Abstract

Efforts to identify driver mutations in cancer have largely focused on genes, whereas non-coding sequences remain relatively unexplored. Here we develop a statistical method based on characteristics known to influence local mutation rate and a series of enrichment filters in order to identify distal regulatory elements harboring putative driver mutations in breast cancer. We identify ten DNase I hypersensitive sites that are significantly mutated in breast cancers and associated with the aberrant expression of neighboring genes. A pan-cancer analysis shows that three of these elements are significantly mutated across multiple cancer types and have mutation densities similar to protein-coding driver genes. Functional characterization of the most highly mutated DNase I hypersensitive sites in breast cancer (using in silico and experimental approaches) confirms that they are regulatory elements and affect the expression of cancer genes. Our study suggests that mutations of regulatory elements in tumors likely play an important role in cancer development.

Original languageEnglish (US)
Article number436
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Deoxyribonuclease I
breast
Genes
cancer
mutations
Breast Neoplasms
Mutation
Neoplasms
genes
Neoplasm Genes
Tumors
Mutation Rate
Statistical methods
oncogenes
Computer Simulation
Gene Expression
coding
tumors
Proteins
proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

D'antonio, M., Weghorn, D., D'antonio-Chronowska, A., Coulet, F., Olson, K. M., Deboever, C., ... Frazer, K. A. (2017). Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. Nature Communications, 8(1), [436]. https://doi.org/10.1038/s41467-017-00100-x

Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. / D'antonio, Matteo; Weghorn, Donate; D'antonio-Chronowska, Agnieszka; Coulet, Florence; Olson, Katrina M.; Deboever, Christopher; Drees, Frauke; Arias, Angelo; Alakus, Hakan; Richardson, Andrea; Schwab, Richard B.; Farley, Emma K.; Sunyaev, Shamil R.; Frazer, Kelly A.

In: Nature Communications, Vol. 8, No. 1, 436, 01.12.2017.

Research output: Contribution to journalArticle

D'antonio, M, Weghorn, D, D'antonio-Chronowska, A, Coulet, F, Olson, KM, Deboever, C, Drees, F, Arias, A, Alakus, H, Richardson, A, Schwab, RB, Farley, EK, Sunyaev, SR & Frazer, KA 2017, 'Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer', Nature Communications, vol. 8, no. 1, 436. https://doi.org/10.1038/s41467-017-00100-x
D'antonio M, Weghorn D, D'antonio-Chronowska A, Coulet F, Olson KM, Deboever C et al. Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. Nature Communications. 2017 Dec 1;8(1). 436. https://doi.org/10.1038/s41467-017-00100-x
D'antonio, Matteo ; Weghorn, Donate ; D'antonio-Chronowska, Agnieszka ; Coulet, Florence ; Olson, Katrina M. ; Deboever, Christopher ; Drees, Frauke ; Arias, Angelo ; Alakus, Hakan ; Richardson, Andrea ; Schwab, Richard B. ; Farley, Emma K. ; Sunyaev, Shamil R. ; Frazer, Kelly A. / Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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