Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer
Year: 2017
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: California Institute for Regenerative Medicine, Deutsche Krebshilfe, National Institutes of Health, University of California, San Diego, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, School of Medicine, University of California, San Diego
Awards: G2714352180, G3033040839, San Diego Clinical and Translational Research Institute, Interdisciplinary Stem Cell Training Program at UCSD II, G429413867, G4366002869, Deciphering the regulatory principles governing enhancer specificity, University of California San Diego Neuroscience Microscopy Imaging Core, G639426234, Training Program in Basic and Clinical Genetics, G7571715736, Specialized Cancer Center Support Grant, G9000255603
OpenAlex ID: W2751578129