Cancer arises through selection of somatic mutations and chromosomal alterations, which can be accelerated by oxidative stress and genotoxicity in an environment of chronic inflammation. Use of aspirin and other NSAIDs has consistently been reported to decrease the incidence of and mortality from a number of cancers, including esophageal adenocarcinoma. The intersection between aspirin and somatic genomic evolution is a complex biological system in which NSAID use introduces new selective pressures that decrease somatic genomic progression to cancer in some patients but not others.
The aims of this study are designed to test the innovative hypothesis that this differential response is due to somatic mutations that govern the molecular mechanisms by which aspirin protects against cancer incidence and mortality. In this application, we propose to employ a classic approach to elucidate molecular mechanisms in complex biological systems: detection and characterization of mutations that alter the biological process. This study will measure somatic mutations by whole exome sequencing in a cohort of 80 individuals with Barrett's esophagus who have been characterized for use of aspirin and other NSAIDs, somatic chromosomal alterations and presence of tetraploidy/aneuploidy.
The first aim will measure exomic mutations in genes that undergo chromosome copy number/LOH at significantly different frequency in regular NSAID users compared to non-users, and in genes that undergo significant chromosome copy number/LOH at early stages of progression beyond 48 months prior to last diagnosis or cancer, as well as test whether aspirin and other NSAIDs decrease the frequency of exomic mutations genome wide.
The second aim will test the interaction between gene mutations and NSAIDs that modulate molecular pathways that prevent genomic instability and progression to cancer in the mutagenic environment of chronic inflammation. Completion of our aims will have a profound impact on research to develop innovative cancer prevention agents by identifying genes and pathways that determine whether a neoplasm will be responsive or non-responsive to NSAIDs as well as determining whether or not NSAIDs reduce exome mutation frequency genome-wide. These advances will allow comparison of different strategies for cancer prevention: personalized prevention that targets specific mutations that confer responsiveness to aspirin and other NSAIDs, and a general strategy for population prevention to reduce overall exome mutation frequency.
People who take non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen have been shown to have a reduced risk of developing cancer, including esophageal cancer (esophageal adenocarcinoma), but how NSAIDs work to reduce this risk and why these drugs are effective in some patients and not others is not well understood. In patients at risk for esophageal adenocarcinoma, we will determine whether aspirin and other NSAIDs prevent gene mutations or are effective only in patients who have certain types of gene mutations. The results of this study will improve our understanding of how aspirin and other NSAIDS work to reduce a person's risk of developing many different types of cancer and will help develop new drugs that can be more effective in reducing cancer risk.
| Reid, Brian J (2017) Genomics, Endoscopy, and Control of Gastroesophageal Cancers: A Perspective. Cell Mol Gastroenterol Hepatol 3:359-366 |
| Reid, Brian J (2016) Surrogate Markers: Lessons from the Next Gen? Cancer Prev Res (Phila) 9:512-7 |
| Kuhner, Mary K; Kostadinov, Rumen; Reid, Brian J (2016) Limitations of the Driver/Passenger Model in Cancer Prevention. Cancer Prev Res (Phila) 9:335-8 |
| Gall, Alevtina; Fero, Jutta; McCoy, Connor et al. (2015) Bacterial Composition of the Human Upper Gastrointestinal Tract Microbiome Is Dynamic and Associated with Genomic Instability in a Barrett's Esophagus Cohort. PLoS One 10:e0129055 |
| Li, Xiaohong; Blount, Patricia L; Reid, Brian J et al. (2014) Quantification of population benefit in evaluation of biomarkers: practical implications for disease detection and prevention. BMC Med Inform Decis Mak 14:15 |
