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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor / genetics*
  • CCCTC-Binding Factor / metabolism*
  • Cell Cycle Proteins / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Cohesins
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Genome, Human
  • Humans
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Promoter Regions, Genetic / genetics
  • Repressor Proteins / genetics

Substances

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Repressor Proteins