RELEVANCE OF GENOMIC ALTERATIONS IN COLORECTAL CANCER

基因组改变与结直肠癌的相关性

• 批准号: 6777645
• 负责人: WALTER J CURRAN
• 金额: $ 1.74万
• 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/6777645
• 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.

目前，结肠癌和直肠癌是美国癌症相关死亡的第二大原因。家族性腺瘤性息肉病(FAP)和遗传性非息肉病性结直肠癌(HNPCC)的个体和家族对这种恶性肿瘤的遗传易感性已被发现。然而，大多数结直肠癌病例似乎是零星的。在FAP基因(结肠腺瘤性息肉病；APC)是第一个或早期事件(非整倍体途径)的个体以及受HNPCC影响的个体(错配修复或MMR途径)中，在理解与肿瘤进展途径相关的遗传变化方面取得了重大进展。这个项目的中心主题是这样一个假设，即肿瘤进展的非整倍体和MMR途径中涉及的基因变化与散发性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个I/II期临床试验，将分别测试直肠癌和转移性结直肠癌患者的多药化疗方案，包括口服药物和OUR，而不使用盆腔放疗。Project的另一个目标是确定患者的治疗可能受到与非整倍体途径(Project 2)或MMR途径(Project 3)或肿瘤进展相关的基因改变的合理影响。预计至少有230名来自临床TRIP参与者的肿瘤将接受MMR状态以及与非整倍体途径相关的基因表达程度的测试。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大肠息肉/肿瘤发展的基因。对MOM1基因和一种新发现的名为MOM2的肿瘤修饰物的进一步研究将进一步深入了解结直肠肿瘤进展的非整倍体途径，以期达到预防和治疗干预的目的。项目3研究人员将继续阐明与错配修复基因相关的结构和功能过程，目前错配修复基因与许多遗传性和散发性结直肠癌的发生和发展有关。这项工作将加深我们对MMR通路中复杂事件的理解，并为结直肠肿瘤的诊断和预后检测提供新的方法。