期刊
CELL SYSTEMS
卷 8, 期 5, 页码 446-+出版社
CELL PRESS
DOI: 10.1016/j.cels.2019.04.001
关键词
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资金
- National Institutes of Health (NIH) through NHGRI [R00HG008171, DP2-HG010099]
- Sidney Kimmel Foundation
- Melanoma Research Alliance
- NIH [R01CA218668-01A1, U24CA210989]
Recent studies have shown that mutations at non-coding elements, such as promoters and enhancers, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF insulators, has been overlooked in the previous driver analyses. We used insulator annotations from CTCF and cohesin ChIA-PET and analyzed somatic mutations in 1,962 whole genomes from 21 cancer types. Using the heterogeneous patterns of transcription-factor-motif disruption, functional impact, and recurrence of mutations, we developed a computational method that revealed 21 insulators showing signals of positive selection. In particular, mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation. Using CRISPR-Cas9, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40%-50%, supporting the role of this boundary element as a cancer driver. Thus, our study reveals several CTCF insulators as putative cancer drivers.
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