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Cell Syst. 2019 May 22;8(5):446-455.e8. doi: 10.1016/j.cels.2019.04.001. Epub 2019 May 8.

Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes.

Author information

1
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
2
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA.
3
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
4
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: ekk2003@med.cornell.edu.

Abstract

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.

KEYWORDS:

CRISPR-Cas9; CTCF/cohesin insulators; TGF-β signaling; mutational signatures; non-coding drivers; pan-cancer analysis

PMID:
31078526
PMCID:
PMC6917527
[Available on 2020-05-22]
DOI:
10.1016/j.cels.2019.04.001
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