Molecular Epidemiology of Esophageal Cancer Prognosis

食管癌预后的分子流行病学

• 批准号: 7417437
• 负责人: GEOFFREY LIU
• 金额: $ 35.68万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417437
• 关键词: Address; Affect; Alleles; Area; Basement membrane; Biological Markers; Biopsy Specimen; CCND1 gene; CYP3A5 gene; Cancer Center; Cancer Patient; Cancer Prognosis; Candidate Disease Gene; Case-Control Studies; Cell Cycle; Chromosomes; Clinical; Computer Simulation; Cyclin D1; DNA Repair; DNA Repair Gene; Data; Disease; ERCC1 gene; ERCC2 gene; Enhancers; Esophageal; Failure; Fluorouracil; Genes; Genetic Polymorphism; Genotype; Glutathione S-Transferase; Goals; Haplotypes; Hematogenous; Immunohistochemistry; Individual; Institution; Lead; Linkage Disequilibrium; Lymphatic Spread; MMP1 gene; MMP3 gene; Malignant Neoplasms; Malignant neoplasm of esophagus; Matrix Metalloproteinases; Measures; Metabolism; Methods; Molecular Epidemiology; Outcome; Pathway interactions; Patients; Platinum Compounds; Polymorphic Microsatellite Marker; Population; Prognostic Factor; Progress Review Group; Progression-Free Survivals; Protein Overexpression; Proteins; Recruitment Activity; Reporting; Research; Research Personnel; Role; Single Nucleotide Polymorphism; Solid Neoplasm; Staining method; Stains; Stomach; Stromelysin 1; TP53 gene; Taxane Compound; Techniques; Thymidylate Synthase; Tissue Banks; Tissues; Toxic effect; Treatment Protocols; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; XRCC1 gene; Xenobiotic Metabolism; cdc Genes; chemotherapy; cohort; follow-up; genetic risk factor; improved; interest; irinotecan; novel; outcome forecast; response; taxane; tumor

DESCRIPTION (provided by applicant): The vast majority of esophageal cancers will develop metastatic disease eventually. Our preliminary data suggest that certain genetic polymorphisms in key pathways may affect survival or prognosis in esophageal and other cancers. Currently, relatively uniform treatment regimens are applied to all patients. A better understanding of the association between germline polymorphisms and prognosis may lead to better treatment strategies and improved outcomes. The proposed study will expand an existing cohort of over 300 esophageal cancer patients established by the Pl's team from 1999-2003 and recruited originally for a pilot case-control study, with the goal of recruiting a total cohort of over 500 patients. Each patient will have a minimum of 3 years of follow-up (and up to 8 years) by the end of the proposed study period. Our overarching aim is to evaluate the roles of genetic polymorphisms in various pathways and their association with esophageal cancer outcomes. The proposed pathways include DNA repair (e.g. ERCC1 ), matrix metalloproteinases, and cell cycle dysregulation (e.g. p53). In addition, polymorphisms of genes involved in the xenobiotic metabolism of commonly-used chemotherapy agents will be assessed, including glutatione stransferases (metabolism of platinum agents), thymidylate synthase (5-fluorouracil), CYP3A5 (taxanes), and UGT1A1 (irinotecan). Outcomes of interest will include disease-free or progression-free survival, and overall survival. To evaluate polymorphisms in linkage disequilibrium, novel in silico haplotyping techniques will be applied. Where feasible, polymorphisms will be correlated with potential biomarkers, such as protein over-expression by immunohistochemical staining. The proposed studies will take advantage of a well-established and well-characterized cohort, an associated extensive pre-treatment tissue bank, and a comprehensive set of preliminary and feasibility results. Furthermore, the proposed studies address directly a prioritized research area identified by the NCI Stomach and Esophageal Cancers Progress Review Group (Year 2002).

描述（由申请人提供）：绝大多数食管癌最终会出现转移性疾病。我们的初步数据表明，关键途径中的某些遗传多态性可能会影响食管和其他癌症的生存或预后。目前，对所有患者都采用了相对均匀的治疗方案。更好地了解种系多态性与预后之间的关联可能会导致更好的治疗策略并改善结果。拟议的研究将扩大现有的组成的300多名PL团队从1999 - 2003年建立的食管癌患者，并最初招募进行试点病例对照研究，目的是招募总共500多名患者。到拟议的研究期结束时，每个患者将至少进行3年的随访（最多8年）。我们的总体目的是评估遗传多态性在各种途径中的作用以及它们与食管癌结果的关联。所提出的途径包括DNA修复（例如ERCC1），基质金属蛋白酶和细胞周期失调（例如p53）。此外，将评估参与常用化学疗法剂异生元代谢的基因的多态性，包括Gloutte stransferase（铂剂的代谢），胸苷酸合酶（5-fluorourouracil），Cyp3A5（Cyp3A5（cyp3a5）（taxanes）和ugtt1a1（ugt1a）（irint1a）。感兴趣的结果将包括无病或无进展的生存以及整体生存。为了评估链接不平衡的多态性，将应用硅单倍型技术中的新型。在可行的地方，多态性将与潜在的生物标志物相关，例如免疫组织化学染色过表达蛋白质。拟议的研究将利用公认且特征良好的队列，相关的广泛的预处理组织库以及一系列全面的初步和可行性结果。此外，拟议的研究直接介绍了NCI胃和食管癌进度审查小组（2002年）确定的优先研究领域。