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A Compendium of Mutational Signatures of Environmental Agents

Jill E Kucab1, Xueqing Zou2, Sandro Morganella3

  • 1Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King's College London, 150 Stamford Street, London SE1 9NH, UK.

Cell
|April 16, 2019
PubMed

Insights

Environmental carcinogens cause distinct DNA mutation patterns in human stem cells. This study identifies specific mutational signatures, revealing cellular repair mechanisms and the direct vulnerability of human DNA to environmental agents.

Area of Science:

  • Genomics
  • Environmental Health
  • Cancer Research

Background:

  • Whole-genome sequencing (WGS) of human tumors reveals mutation patterns linked to cancer origins.
  • Understanding environmental exposures is crucial for identifying cancer-causing agents.

Purpose of the Study:

  • To investigate mutational signatures in human stem cells exposed to environmental carcinogens.
  • To characterize DNA repair pathways involved in resolving mutagen-induced damage.

Main Methods:

  • Whole-genome sequencing (WGS) of 324 human-induced pluripotent stem cell lines.
  • Exposure of stem cells to 79 known or suspected environmental carcinogens.
  • Analysis of mutational signatures, including substitutions, double-substitutions, and insertions/deletions (indels).

Main Results:

  • Forty-one carcinogens induced characteristic substitution mutational signatures, some mirroring those in human tumors.
  • Six agents produced double-substitution signatures, and eight produced indel signatures.
  • Mutation asymmetry analysis confirmed functional mismatch and transcription-coupled DNA repair pathways.

Conclusions:

  • Environmental mutagens induce diverse mutational signatures in human stem cells via various repair pathways.
  • This compendium aids in exploring environmental factors in cancer etiology.
  • Human stem cell DNA is directly vulnerable to environmental agents.
Keywords:
DNA damageMutational signaturescarcinogensenvironmental mutagensmutagenesis

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