A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

Original languageEnglish (US)
Pages (from-to)386-399.e12
JournalCell
Volume173
Issue number2
DOIs
StatePublished - Apr 5 2018

Fingerprint

Genes
Tumors
Neoplasms
Computational methods
Chromatin
Chemical activation
RNA
Tissue
Messenger RNA
Aneuploidy
DNA
Immunotherapy
Genome
Mutation

Keywords

  • aneuploidy
  • chromatin state
  • enhancer expression
  • mutation burden
  • pan-cancer analysis
  • PD-L1 expression
  • prognostic markers
  • The Cancer Genome Atlas

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples. / The Cancer Genome Atlas Research Network.

In: Cell, Vol. 173, No. 2, 05.04.2018, p. 386-399.e12.

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network 2018, 'A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples', Cell, vol. 173, no. 2, pp. 386-399.e12. https://doi.org/10.1016/j.cell.2018.03.027
The Cancer Genome Atlas Research Network. / A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples. In: Cell. 2018 ; Vol. 173, No. 2. pp. 386-399.e12.
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N2 - The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

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