Universität zu Köln

D' Antonio, Matteo, Weghorn, Donate, D' Antonio-Chronowska, Agnieszka, Coulet, Florence, Olson, Katrina M., DeBoever, Christopher ORCID: 0000-0002-1901-2576, Drees, Frauke, Arias, Angelo, Alakus, Hakan, Richardson, Andrea L., Schwab, Richard B., Farley, Emma K., Sunyaev, Shamil R. and Frazer, Kelly A. (2017). Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code D' Antonio, Matteo UNSPECIFIED UNSPECIFIED UNSPECIFIED Weghorn, Donate UNSPECIFIED UNSPECIFIED UNSPECIFIED D' Antonio-Chronowska, Agnieszka UNSPECIFIED UNSPECIFIED UNSPECIFIED Coulet, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Olson, Katrina M. UNSPECIFIED UNSPECIFIED UNSPECIFIED DeBoever, Christopher UNSPECIFIED orcid.org/0000-0002-1901-2576 UNSPECIFIED Drees, Frauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Arias, Angelo UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, Hakan UNSPECIFIED UNSPECIFIED UNSPECIFIED Richardson, Andrea L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwab, Richard B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Farley, Emma K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sunyaev, Shamil R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frazer, Kelly A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-218038
DOI:	10.1038/s41467-017-00100-x
Journal or Publication Title:	Nat. Commun.
Volume:	8
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SOMATIC MUTATIONS; CHROMATIN ORGANIZATION; SENSITIVE DETECTION; HUMAN GENOME; LANDSCAPE; DATABASE; PROTEIN Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21803