Prof. John M. Essigmann, Leader
Department of Biological Engineering
Department of Chemistry
Robert G. Croy, Key Personnel
Department of Bioimaging and Chemical Analysis
Prof. Forest M. White, Team Member
Department of Biological Engineering

High Resolution Mutation Spectra and Multi-Omics for Deducing Etiology and Predicting Disease


The goal of Project 2 is to identify mechanistic links at the genomic and cell signaling network-levels between exposure to NDMA, or a mixture of NDMA with other chemicals found at a Superfund site, and the initiation and progression phases of carcinogenesis.


People living near a local Superfund site asked our Community Engagement Core if there were biomarkers that could help explain and predict their risk of cancer. We apply a new DNA sequencing tool that is 104 fold more accurate than conventional sequencing methods, state-of-the-art DNA adduct measurement tools, and high-resolution phosphoproteomic technology to evaluate the pathways leading to cancer by NDMA and related compounds. We utilize C-GEM mice (Project 1) and cells derived from those mice as our biological model systems. While the project focuses on NDMA at present, it will progress to study the toxicological effects of other compounds of interest at the Superfund site. Ultimately, the genomic, adductomic, and signaling networks probed could identify valuable early-onset biomarkers that portend later life diseases. In addition, these biomarkers will be used to determine if mitigation measures can trigger protective pathways in animals and, eventually, people.

The Project

Project 2 tests the hypothesis that the patterns of mutations observed, and/or the patterns of phosphoproteomic networks disrupted are mechanism-based biomarkers that can be used to understand, detect, and possibly prevent disease. Project 2 uses high resolution mutational spectra and high-resolution proteomic patterns of specific chemicals with hopes to detect mechanistically interpretable and unique records that reflect environmental exposures that trigger specific human diseases. In sum, Project 2 attempts to establish biological plausibility between environmental stressors at Superfund sites and resulting diseases, most notably, cancer.

  • Aim 1: To define the DNA adduct profiles and mutational spectra induced by N-nitrosamines in male and female mice treated with acute and long-term low dosing regimens.
    Hypothesis: The high-resolution mutational spectrum of NDMA will be a distinctive biomarker to help epidemiologists link exposure to disease.
  • Aim 2: To record mutational spectra of Superfund toxicants in mammalian cell culture.
    Hypothesis: The study of environmental nitrosamines in mammalian cells that have defined genetic backgrounds can provide information that complements animal studies and helps support clinical relevance.
  • Aim 3: To perform systems level phosphoproteomic analysis of cellular responses to NDMA and other N-nitrosamines.
    Hypothesis: By quantifying both the DNA damage response and general adaptive response, we can flesh out the Adverse Outcome Pathway of NDMA – i.e., the mechanisms regulating cell survival, proliferation, migration, and potentially oncogenic transformation in response to NDMA and other N-nitrosamines exposure.