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

描述（由申请人提供）：癌症通过选择体细胞突变和染色体改变而产生，在慢性炎症环境中，氧化应激和遗传毒性可加速癌症的发生。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许多癌症的发病率和死亡率，包括食管腺癌。阿司匹林和体细胞基因组进化之间的交叉是一个复杂的生物系统，其中NSAID的使用引入了新的选择性压力，这些压力降低了某些患者的体细胞基因组向癌症的进展，而不是其他患者。本研究的目的是测试创新的假设，即这种差异反应是由于 体细胞突变控制阿司匹林预防癌症发生和死亡的分子机制。在这个应用中，我们建议采用经典的方法来阐明复杂的生物系统中的分子机制：检测和表征改变生物过程的突变。本研究将通过全外显子组测序测量80名Barrett食管患者的体细胞突变，这些患者的特征是使用阿司匹林和其他NSAID、体细胞染色体改变和存在四倍体/非整倍体。第一个目的是测量与非使用者相比，在常规NSAID使用者中以显著不同的频率经历染色体拷贝数/洛的基因中的外显子组突变，以及在最后诊断或癌症之前超过48个月的进展早期阶段经历显著染色体拷贝数/洛的基因中的外显子组突变，以及测试阿司匹林和其他NSAID是否降低全基因组外显子组突变的频率。第二个目标将测试基因突变和NSAID之间的相互作用，这些NSAID调节分子途径，防止基因组不稳定性和慢性炎症致突变环境中的癌症进展。我们的目标的完成将对研究产生深远的影响，以开发创新的癌症预防药物，通过识别基因和途径，确定肿瘤是否对NSAID有反应或无反应，以及确定NSAID是否降低全基因组外显子组突变频率。这些进展将允许比较不同的癌症预防策略：针对特定突变的“个性化”预防，这些突变赋予阿司匹林和其他NSAID的反应性，以及用于人群预防的一般策略，以降低总体外显子组突变频率。

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.