Project Details
Description
The goal of our research is to chemically characterize DNA adducts associated with specific human cancers.
We will link this structural information to novel mutational patterns identified during this research. These melded
data should facilitate significantly the identification of environmental, dietary and endogenous agents responsible
for human cancers. The proposed research focuses on renal and urological cancers; specifically, clear-cell renal
cell carcinomas, carcinomas of the upper urinary tract and bladder cancer. Additionally, we will attempt to detect
and, if possible, quantify single or multiple DNA adducts found in exfoliated urinary cells as an initial step in
developing a noninvasive biomarker for carcinogen screening.
In this research, we utilize sensitive, mass spectrometry techniques to detect and quantify multiple DNA
adducts in target tissues and urinary cells. For screening purposes, we will employ ultraperformance liquid
chromatography/multistage scan mass spectrometry (UPLC/MSn), using a linear quadrupole ion trap mass
spectrometer. The use of UPLC/MSn permits quantitation of known adducts and characterization of unknown
adducts, the latter by acquiring MS3 scan stage product ion spectra. We have employed this approach
successfully to identify single and multiple DNA adducts in human tissues, saliva, and exfoliated urinary cells.
In Aim 1, we use data-dependent and independent scanning methods to optimize detection of DNA adducts
derived from genotoxins found in tobacco smoke and in the diet; also from electrophiles that are produced
endogenously by oxidative processes. In Aim 2, we employ targeted as well as data-dependent and independent
“adductomics” approaches, using UPLC/MSn to screen DNA adducts formed in the kidney, upper urothelial tract,
bladder, and cells in the urine of patients with target cancers. In Aim 3, we conduct deep sequencing of DNA
isolated from tumor and non-tumor tissues to identify mutational patterns that may be linked to specific DNA
adducts, chemical exposures or aberrant endogenous processes.
Our research has significant implications for public health. DNA adduct and mutational data are of high
translational impact and provide an understanding of exposures to hazardous chemicals that can initiate cancer
in humans. By linking these methods, we create a molecular approach that provides clues to the identity of
environmental, dietary and endogenous carcinogens and establishes biomarkers of exposure that can be used
in epidemiologic studies to identify populations at risk. Once identified, pragmatic measures can be taken to
reduce human exposure to these chemicals, by changes in life-style and/or diet, which are probably the most
efficient means of chemoprevention.
Status | Finished |
---|---|
Effective start/end date | 6/20/17 → 6/30/23 |
Funding
- National Cancer Institute: $609,040.00
- National Cancer Institute: $245,714.00
- National Cancer Institute: $578,352.00
- National Cancer Institute: $596,240.00
- National Cancer Institute: $596,240.00
- National Cancer Institute: $343,515.00
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