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Massachusetts Institute of Technology

Superfund Research Program

Assessment of Genotoxic Health Risks at Superfund Sites through Mutational Signatures

Project Leader: John M. Essigmann
Co-Investigator: Robert G. Croy
Grant Number: P42ES027707
Funding Period: 2017-2022
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2017-2022)

Exposure of people to single chemicals or mixtures at Superfund sites has unquestionably occurred. The unanswered question being addressed here is whether those exposures can be associated with genetic risk, which would provide biological plausibility to the argument that the chemicals in the environment have affected human health and welfare. The compounds chosen for investigation were inspired by engagement efforts in several local communities containing Superfund sites. Carcinogenic N-nitrosamines (e.g., N-nitrosodimethylamine or NDMA) are abundant at one or more of the sites in their catchment area.

As part of the Massachusetts Institute of Technology Superfund Research Program (MIT SRP) Center, this project has three components:

  • A genetically engineered mouse that responds to environmental toxicants in a manner that predicts end-stage cancers
  • A newly developed high-fidelity DNA sequencing procedure that provides unprecedentedly high-resolution mutational spectra (HRMS)
  • A novel computational module that quantitatively compares HRMS from their mouse model with the rapidly expanding data set of The Cancer Genome Atlas Project (TCGA) and other tumor sequencing efforts

In preliminary work, the technology was tested using a natural liver carcinogen. The results convincingly show that their murine HRMS, as early as 10 weeks after toxin administration, are nearly identical to computationally extracted mutational patterns from human liver cancer. This short time frame enables the mechanistically detailed investigations of the role of gene-environment interactions as a contributor to cancer burden.

The research team is examining the "exposure mutational spectra" of NDMA. They also longitudinally track mutational spectra up to the development of tumors. It is expected that mutagenic processes independent of the initiating agent super-impose their spectra on the early "exposure spectrum." Informatics techniques establish the extent of quantitative cosine similarity of the murine spectra with human tumor spectra mined from TCGA. The researchers are also probing gene-environment interactions. The role of specific DNA damage response processes as molders of their HRMS is also being evaluated.

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