Molecular Epidemiology of Esophageal Cancer Prognosis

食管癌预后的分子流行病学

• 批准号: 6813650
• 负责人: GEOFFREY LIU
• 金额: $ 44.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6813650
• 关键词: DNA binding protein; DNA repair; antineoplastics; biomarker; cell cycle proteins; cisplatin; clinical research; drug metabolism; esophagus neoplasm; fluorouracil; genetic polymorphism; human genetic material tag; human subject; human therapy evaluation; metalloendopeptidases; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer epidemiology; neoplasm /cancer genetics; outcomes research; paclitaxel; patient care management; patient oriented research; prognosis; thymidylate synthase

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都会发展为转移性疾病。我们的初步数据表明，关键通路中的某些遗传多态性可能会影响食管癌和其他癌症的生存或预后。目前，所有患者均采用相对统一的治疗方案。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和改善的结果。拟议的研究将扩大 Pl 团队在 1999 年至 2003 年建立的现有 300 多名食管癌患者队列，最初是为了试点病例对照研究而招募的，目标是招募总共 500 多名患者的队列。在建议的研究期结束时，每位患者将接受至少 3 年（最长 8 年）的随访。我们的首要目标是评估遗传多态性在各种途径中的作用及其与食管癌结果的关联。提议的途径包括 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，还将评估常用化疗药物的异生素代谢相关基因的多态性，包括谷胱甘肽转移酶（铂类药物的代谢）、胸苷酸合成酶（5-氟尿嘧啶）、CYP3A5（紫杉烷）和UGT1A1（伊立替康）。感兴趣的结果将包括无病或无进展生存期以及总生存期。为了评估连锁不平衡中的多态性，将应用新颖的计算机单元分型技术。在可行的情况下，多态性将与潜在的生物标志物相关，例如通过免疫组织化学染色的蛋白质过度表达。拟议的研究将利用一个完善且特征明确的队列、一个相关的广泛的治疗前组织库以及一套全面的初步和可行性结果。此外，拟议的研究直接涉及 NCI 胃癌和食道癌进展审查小组（2002 年）确定的优先研究领域。