Related Experiment Video

Updated: Jun 26, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer

Lee J Pribyl1, Jennifer E Kay1,2, Joshua J Corrigan1

  • 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.

NAR Cancer
|June 25, 2026
PubMed

Insights

Early exposure to the carcinogen NDMA significantly increases liver tumors in mice lacking DNA repair. This damage triggers inflammation and cell growth, promoting cancer development.

Area of Science:

  • Hepatocarcinogenesis research
  • Environmental toxicology
  • DNA repair mechanisms

Background:

  • N-Nitrosodimethylamine (NDMA) is a probable human carcinogen.
  • NDMA induces DNA adducts repaired by O6-methylguanine-DNA methyltransferase (MGMT).
  • Early-life mutagen exposure can promote latent liver tumorigenesis.

Purpose of the Study:

  • To investigate how early-life NDMA exposure promotes liver tumorigenesis.
  • To elucidate the role of MGMT in mediating NDMA-induced hepatocarcinogenesis.
  • To identify molecular mechanisms linking mutagen exposure to liver cancer.

Main Methods:

  • Longitudinal studies in wild-type and MGMT-deficient (Mgmt-/-) mice.
  • NDMA administration on postnatal days 8 and 15.
  • Multi-omics profiling (phenomics, transcriptomics, phosphoproteomics, spatial transcriptomics) and histopathology.

Main Results:

  • NDMA exposure caused a nine-fold increase in liver tumors in Mgmt-/- mice.
  • Elevated O6MeG adducts, sustained γH2AX activation, and micronucleus formation were observed.
  • Persistent interferon response, immune cell infiltration, and clonal expansion were prominent in Mgmt-/- mice.
  • Spatial transcriptomics revealed activation of oncogenic and inflammatory pathways in clonally expanded cells.

Conclusions:

  • Acute early-life NDMA exposure drives persistent DNA damage signaling, chronic interferon activation, and clonal expansion.
  • These processes promote MGMT-dependent hepatocarcinogenesis.
  • Early mutagen exposure links to long-term premalignant evolution and tumor emergence, identifying biomarkers and interception targets for NDMA-induced liver cancer.

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