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HYENA detects oncogenes activated by distal enhancers in cancer

Anqi Yu1, Ali E Yesilkanal1, Ashish Thakur2

  • 1Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.

Nucleic Acids Research
|July 25, 2024
PubMed

Insights

We developed HYENA, a computational tool to find oncogenes activated by enhancer hijacking in cancer. This method identified 108 candidate oncogenes, including non-coding genes like TOB1-AS1, which promotes pancreatic cancer metastasis.

Area of Science:

  • Genomics
  • Cancer Biology
  • Bioinformatics

Background:

  • Somatic structural variations (SVs) can alter genome organization and gene regulation in cancer.
  • Enhancer hijacking, driven by SVs, activates proto-oncogenes, but studies often overlook non-coding genes.
  • Understanding SV-driven oncogene activation is crucial for cancer research.

Purpose of the Study:

  • To develop a computational algorithm (HYENA) for identifying candidate oncogenes (protein-coding and non-coding) activated by enhancer hijacking.
  • To analyze a large cohort of adult tumors to discover novel oncogenes implicated in enhancer hijacking.
  • To investigate the role of specific non-coding genes, such as TOB1-AS1, in cancer progression.

Main Methods:

  • Development of the HYENA computational algorithm integrating whole-genome and transcriptome sequencing data.
  • Application of a rank-based regression model to associate gene expression with somatic SVs.
  • Systematic analysis of 1146 tumors across 25 adult cancer types.

Main Results:

  • Identification of 108 candidate oncogenes activated by enhancer hijacking, including numerous non-coding genes.
  • Discovery of the long non-coding RNA TOB1-AS1 activated by SVs in 10% of pancreatic cancers via 3D genome alterations.
  • Demonstration that high TOB1-AS1 expression promotes cancer cell invasion and metastasis.

Conclusions:

  • HYENA is effective in identifying novel oncogenes, particularly non-coding ones, activated by enhancer hijacking.
  • Genetic alterations in non-coding regions significantly contribute to tumorigenesis and cancer progression.
  • TOB1-AS1 represents a potential therapeutic target in pancreatic cancer due to its role in metastasis.

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