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Nat Commun. 2017 Sep 5;8(1):436. doi: 10.1038/s41467-017-00100-x.

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

Author information

1
Moores Cancer Center, University of California, La Jolla, San Diego, CA, 92093, USA.
2
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
3
Institute for Genomic Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
4
Department of Pediatrics, University of California, La Jolla, San Diego, CA, 92093, USA.
5
Department of Genetics, Pitie-Salpetriere Hospital, Pierre and Marie Curie University, Paris, 75013, France.
6
Department of Medicine, Division of Cardiology, University of California, La Jolla, San Diego, CA, 92093, USA.
7
Division of Biological Sciences, Section of Molecular Biology, University of California, La Jolla, San Diego, CA, 92093, USA.
8
Bioinformatics and Systems Biology, University of California, La Jolla, San Diego, CA, 92093, USA.
9
Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, 50937, Germany.
10
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
11
The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
12
Department of Medicine, School of Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
13
Department of Medicine, Division of Cardiology, University of California, La Jolla, San Diego, CA, 92093, USA. efarley@ucsd.edu.
14
Division of Biological Sciences, Section of Molecular Biology, University of California, La Jolla, San Diego, CA, 92093, USA. efarley@ucsd.edu.
15
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. ssunyaev@rics.bwh.harvard.edu.
16
Moores Cancer Center, University of California, La Jolla, San Diego, CA, 92093, USA. kafrazer@ucsd.edu.
17
Institute for Genomic Medicine, University of California, La Jolla, San Diego, CA, 92093, USA. kafrazer@ucsd.edu.
18
Department of Pediatrics, University of California, La Jolla, San Diego, CA, 92093, USA. kafrazer@ucsd.edu.

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.Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I hypersensitive sites in breast cancer and experimentally demonstrate they are regulatory elements of known cancer genes.

PMID:
28874753
PMCID:
PMC5585396
DOI:
10.1038/s41467-017-00100-x
[Indexed for MEDLINE]
Free PMC Article

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