Project 3: Mutations
Leveraging high resolution mutation spectra to deduce prior exposure to environmental mutagens, with a focus on benzo[a]pyrene and N-nitrosodimethylamine (NDMA).
PROJECT LEADERS: BOB CROY, JOHN ESSIGMANN
Exposure of people to single chemicals or mixtures at Superfund sites has unquestionably occurred. The unanswered question is whether those exposures can be associated with genetic mutations, which would contribute 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) and polycyclic aromatic hydrocarbons (PAHs) are abundant at the Olin, Industriplex, Wells G&H, and Loring Air Force Base Superfund Sites.
A newly developed high-fidelity DNA sequencing procedure provides unprecedentedly high-resolution mutational spectra (HRMS), and a novel computational module enables quantitative comparison of HRMS from experimental mice with the rapidly expanding data set of The Cancer Genome Atlas Project (TCGA).
In preliminary work, the technology was tested using a natural liver carcinogen. The results convincingly show that murine HRMS, as early as 10 weeks after toxin administration, are nearly identical to computationally extracted mutational patterns from human liver cancer.
Project 3 is examining the “exposure mutational spectra” of NDMA as an individual compound and in mixtures. Informatics techniques will establish the extent of quantitative cosine similarity of the murine mutation spectra with human tumor mutation spectra mined from TCGA. The roles of specific DNA damage response processes in influencing HRMS are also being evaluated.