Identification of cancer drivers at CTCF insulators in 1,962 whole genomes Journal Article
| Authors: | Liu, E. M.; Martinez-Fundichely, A.; Diaz, B. J.; Aronson, B.; Cuykendall, T.; MacKay, M.; Dhingra, P.; Wong, E. W. P.; Chi, P.; Apostolou, E.; Sanjana, N. E.; Khurana, E. |
| Article Title: | Identification of cancer drivers at CTCF insulators in 1,962 whole genomes |
| 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. © 2019 The Authors We developed a computational method that combines recurrence and functional impact of mutations to identify cancer drivers. Application of the method on 1,962 cancer whole genomes reveals putative drivers at CTCF insulators. In particular, mutations in an insulator on chr19 are associated with TGFB1 up-regulation and may point to a novel mechanism of TGF-β signaling modulation in multiple cancer types. © 2019 The Authors |
| Keywords: | promoter region; somatic mutation; nonhuman; cohesin; chromosome structure; melanoma; cell growth; chromatin immunoprecipitation; gene identification; human genome; telomerase reverse transcriptase; transforming growth factor beta1; mutation rate; multiple cancer; mutagenesis; enhancer region; insulator element; guide rna; transcription factor ctcf; human; priority journal; article; whole genome sequencing; tgf-β signaling; crispr-cas9; mutational signatures; gene editing; crispr-cas9 system; malignant neoplasm; pan-cancer analysis; ctcf/cohesin insulators; non-coding drivers |
| Journal Title: | Cell Systems |
| Volume: | 8 |
| Issue: | 5 |
| ISSN: | 2405-4712 |
| Publisher: | Cell Press |
| Date Published: | 2019-05-22 |
| Start Page: | 446 |
| End Page: | 455.e8 |
| Language: | English |
| DOI: | 10.1016/j.cels.2019.04.001 |
| PUBMED: | 31078526 |
| PROVIDER: | scopus |
| PMCID: | PMC6917527 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 June 2019 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work