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Åke Borg

Åke Borg

Principal investigator

Åke Borg

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

Author

  • Yiqun Zhang
  • Fengju Chen
  • Nuno A Fonseca
  • Yao He
  • Masashi Fujita
  • Hidewaki Nakagawa
  • Zemin Zhang
  • Alvis Brazma
  • Chad J Creighton

Other contributions

  • Åke Borg
  • Markus Ringnér
  • Johan Staaf

Summary, in English

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.

Department/s

  • LUCC: Lund University Cancer Centre
  • Familial Breast Cancer
  • Breastcancer-genetics
  • Molecular Cell Biology
  • Breast/lungcancer
  • Research Group Lung Cancer

Publishing year

2020-02-05

Language

English

Publication/Series

Nature Communications

Volume

11

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

Keywords

  • DNA Methylation
  • Databases, Genetic
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Genomic Structural Variation
  • Humans
  • Neoplasms/genetics
  • Oncogenes
  • Regulatory Sequences, Nucleic Acid
  • Whole Genome Sequencing

Status

Published

Research group

  • Familial Breast Cancer
  • Research Group Lung Cancer

ISBN/ISSN/Other

  • ISSN: 2041-1723