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

描述(申请人提供)：癌症是通过选择体细胞突变和染色体改变而产生的，在慢性炎症环境中，氧化应激和遗传毒性会加速癌症的发生。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包括食管腺癌在内的一些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，在这个系统中，非甾体抗炎药的使用带来了新的选择压力，减少了一些患者的体细胞基因组向癌症的进展，但不是另一些患者。这项研究的目的是检验创新假设，即这种差异反应是由于 控制阿司匹林预防癌症发病率和死亡率的分子机制的体细胞突变。在这一应用中，我们建议使用一种经典的方法来阐明复杂生物系统中的分子机制：检测和表征改变生物过程的突变。这项研究将通过整个外显子组测序来检测80名Barrett食管症患者的体细胞突变，这些患者的特征是使用阿司匹林和其他非类固醇抗炎药，体细胞染色体改变和存在四倍体/非整倍体。第一个目标将测量常规非类固醇抗炎药使用者与非使用者相比，发生染色体拷贝数/杂合性缺失频率显著不同的基因的外显体突变，以及在最后诊断或癌症前48个月以上的早期进展阶段经历显著染色体拷贝数/杂合性缺失的基因中的外显性突变，以及测试阿司匹林和其他非类固醇抗炎药是否降低全基因组外显性突变的频率。第二个目标将测试基因突变和非甾体抗炎药之间的相互作用，这些基因突变和非甾体抗炎药调节分子通路，防止基因组不稳定和在慢性炎症的突变环境中进展为癌症。我们的目标的实现将对开发创新的癌症预防药物的研究产生深远的影响，通过识别决定肿瘤对非类固醇抗炎药是否有效的基因和途径，以及确定非类固醇抗炎药是否在全基因组范围内降低外显子突变频率。这些进展将使癌症预防的不同策略得以比较：针对阿司匹林和其他非类固醇抗炎药的特定突变的“个性化”预防，以及降低总体外显子突变频率的总体人口预防战略。

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.