(PQA1) Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention

描述（由申请人提供）：癌症是通过体细胞突变和染色体改变的选择而产生的，在慢性炎症环境中，氧化应激和遗传毒性可以加速这一过程。阿司匹林和其他非甾体抗炎药的使用一直被报道可以降低包括食管癌在内的许多癌症的发病率和死亡率。阿司匹林和体细胞基因组进化之间的交集是一个复杂的生物系统，其中非甾体抗炎药的使用引入了新的选择压力，在一些患者中减少了体细胞基因组进展为癌症，而在其他患者中则没有。本研究的目的是为了检验创新的假设，这种差异反应是由于

DESCRIPTION (provided by applicant): 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.