RELEVANCE OF GENOMIC ALTERATIONS IN COLORECTAL CANCER

基因组改变与结直肠癌的相关性

• 批准号: 6493131
• 负责人: WALTER J CURRAN
• 金额: $ 4.71万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493131
• 关键词: colorectal neoplasms; neoplasm /cancer genetics

Carcinoma of the colon and rectum is currently the second leading cause of cancer-related mortality in the United States. Genetic susceptibility to this malignancy has been identified among individuals and families with familial adenomatous polyposis (FAP) and with hereditary non-polyposis colorectal cancer (HNPCC). However, the majority of colorectal cancer cases appear sporadic. There have been significant advances in understanding the genetic alterations associated with tumor progression pathways among individuals where the FAP gene (adenomatous polyposis coli; APC) is the first or an early event (the Aneuploid Pathway) as well as among HNPCC-affected individuals (the Mismatch Repair or MMR-Pathway). Central to the theme of this project is the hypothesis that the genetic alterations implicated in the Aneuploid- and MMR-Pathways of tumor progression are relevant to the diagnostic and therapeutic approaches of patients with sporadic colorectal cancers. This Program consists of three Projects of three Projects and three Core facilities. Project 1 has nine phase I/II clinical trials which will test multi- agent chemotherapy regimens including oral agents with our without pelvic radiation for patients with rectal cancer or metastatic colorectal cancer, respectively. Another goal of Project is to identify patients whose therapy an be rationally influenced by determination of genetic alterations associated with the Aneuploid-Pathway (Project 2) or MMR-pathway (Project 3) or tumor progression. It is expected that at least 230 tumors form clinical trip enrollees will be tested for MMR Status as well as the degree of expression of genes related to the Aneuploid Pathway. Investigators in Project 2 will use the APC system to further identify and characterize genes that influence the development of colorectal polyps/tumors. Additional studies of the Mom1 locus and a newly discovered tumor modifier named Mom2 will provide further insight into the Aneuploid-Pathway of colorectal tumor progression with the goal of prevention and therapeutic intervention. Project 3 researchers will continue to elucidate the structural and functional processes associated with mismatch repair genes now implicated in the development and progression of many hereditary and sporadic colorectal cancers. This work will enhance our understanding of the complex events in the MMR-pathway and also provide new diagnostic and prognostic methodologies to test in colorectal tumors.

结肠癌和直肠癌目前是美国与癌症相关死亡率的第二大原因。在具有家族性腺瘤性息肉病（FAP）和遗传性非poly型大肠癌（HNPCC）的个体和家族中，已经发现了对这种恶性肿的遗传敏感性。但是，大多数结直肠癌病例似乎零星。在理解与FAP基因（腺瘤性息护物大肠杆菌; APC）的个体之间与肿瘤进展途径相关的遗传变化方面取得了重大进展，是第一个或早期事件（Aneuploid途径）以及受HNPCC影响的个体（不匹配修复或MMR-Pathway）。该项目主题的核心是假设，即肿瘤进展的非整倍体和MMR pathways的遗传改变与零星结直肠癌患者的诊断和治疗方法有关。该计划由三个项目和三个核心设施组成。项目1有9阶段I/II期临床试验，该试验将分别针对直肠癌或转移性结直肠癌的患者进行多药化疗方案，包括我们无骨盆辐射的口服药物。项目的另一个目标是确定其治疗因确定与非整倍体 - 途径（Project 2）或MMR Pathway（项目3）或肿瘤进展相关的遗传变化而在理性上的治疗的患者。预计将至少230个肿瘤形成临床旅行的参与者的MMR状态以及与非整倍体途径相关的基因的表达程度。项目2中的研究人员将使用APC系统进一步识别和表征影响结直肠息肉/肿瘤发展的基因。对MOM1基因座和名为MOM2的新发现的肿瘤修饰剂的其他研究将进一步深入了解结直肠肿瘤进展的非整倍体 - 途径，以预防和治疗干预。项目3研究人员将继续阐明与现在有关许多遗传和零星结直肠癌的发展和发展的不匹配修复基因相关的结构和功能过程。这项工作将增强我们对MMR-Pathway中复杂事件的理解，还提供了新的诊断和预后方法，以测试结直肠肿瘤。