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.
CITATION STYLE
Liu, E. M., Martinez-Fundichely, A., Diaz, B. J., Aronson, B., Cuykendall, T., MacKay, M., … Khurana, E. (2019). Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes. Cell Systems, 8(5), 446-455.e8. https://doi.org/10.1016/j.cels.2019.04.001
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