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

(PQA1) 阿司匹林与炎症：突变、基因、途径和预防

• 批准号: 8723785
• 负责人: Xiaohong Li
• 金额: $ 46.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723785
• 关键词: Address; Aneuploidy; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Barrett Esophagus; Biological Process; Biopsy; Chemopreventive Agent; Chromosome abnormality; Chromosomes; Chronic; Colorectal Cancer; Detection; Development; Diagnosis; Drug usage; Drug user; Environment; Esophageal Adenocarcinoma; Evolution; Failure; Frequencies; Gene Mutation; Genes; Genome; Genomic Instability; Genomics; Ibuprofen; Incidence; Individual; Induced Mutation; Inflammation; Inflammatory; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of esophagus; Measures; Metformin; Modeling; Molecular; Mutation; Neoplasms; Outcome; Outcome Study; Oxidative Stress; PIK3CA gene; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Population; Prevention; Reporting; Research; Research Design; Rest; Risk; Sampling; Somatic Mutation; Staging; Testing; Tetraploidy; Work; cancer diagnosis; cancer prevention; cancer risk; cancer type; cohort; complex biological systems; exome; exome sequencing; genome-wide; genotoxicity; improved; in vivo; innovation; mortality; pressure; prevent; progression marker; public health relevance; response; tumor progression

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.

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，慢性炎症环境中的氧化应激和基因毒性会加速癌症的发生。据报道，使用阿司匹林和其他非甾体抗炎药可以降低多种癌症（包括食管腺癌）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叉点是一个复杂的生物系统，其中 NSAID 的使用引入了新的选择压力，可以减少某些患者而非其他患者的体细胞基因组进展为癌症。本研究的目的旨在检验这一创新假设，即这种差异反应是由于 体细胞突变控制着阿司匹林预防癌症发生和死亡的分子机制。在此应用中，我们建议采用经典方法来阐明复杂生物系统中的分子机制：改变生物过程的突变的检测和表征。这项研究将通过全外显子组测序来测量 80 名巴雷特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非甾体抗炎药、体细胞染色体改变以及四倍体/非整倍体的存在。第一个目标是测量常规 NSAID 使用者与非使用者相比发生染色体拷贝数/LOH 频率显着不同的基因的外显子突变，以及在超过 48 个月的进展早期阶段发生显着染色体拷贝数/LOH 的基因的外显子突变最后诊断或癌症，以及测试阿司匹林和其他非甾体抗炎药是否会降低全基因组外显子突变的频率。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，这些药物调节分子途径，在慢性炎症的诱变环境中防止基因组不稳定和进展为癌症。我们的目标的完成将对开发创新型癌症预防药物的研究产生深远的影响，通过识别基因和途径来确定肿瘤是否对非甾体抗炎药有反应或无反应，以及确定非甾体抗炎药是否会降低外显子组突变频率。宽的。这些进展将允许比较不同的癌症预防策略：针对赋予阿司匹林和其他非甾体抗炎药反应性的特定突变的“个性化”预防，以及降低总体外显子组突变频率的总体预防策略。