Identification of Cancer Drivers at CTCF Insulators in 1,962 Whole Genomes Academic Article uri icon

Overview

MeSH Major

  • Athletic Injuries
  • Cartilage, Articular
  • Orthopedic Procedures
  • Return to Sport

abstract

  • © 2019 The Authors 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.

publication date

  • May 22, 2019

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1016/j.cels.2019.04.001

Additional Document Info

start page

  • 446

end page

  • 455.e8

volume

  • 8

number

  • 5