COLON TUMOR PROJECT

NCI主任向科学界提出了挑战，要求他们利用现有和开发中的技术来生成人类肿瘤分子变化的全面概况，以便定义临床上相关的分子肿瘤“特征”。在这个项目中，我们将对结直肠癌的基因和蛋白表达进行全面的研究。结直肠癌是西方世界癌症发病率和死亡率的主要原因，在美国每年约有14万新发病例和5.6万人死亡。与其他常见的上皮性癌症一样，它的发展是复杂的，其病因和发病机制的完整解释仍然难以捉摸。原癌基因和抑癌基因突变的积累有助于腺瘤病变的开始和向癌症的进展。尽管癌症遗传学取得了进展，但仍有大量工作要做。密歇根大学正在进行一项名为“结直肠癌分子流行病学(MECC)”的研究。MECC项目是一项以人群为基础的病例对照研究，考察了结直肠癌发生中的遗传序列变异和环境因素。在这项合作研究中，将确定2100例结直肠癌病例。除了采集正常组织和肿瘤组织外，还收集和储存每个病例的外周血液和血清。进行详细的组织病理学研究，并获得流行病学危险因素信息。此外，对于这里提出的工作来说，对进入MECC研究的患者的临床随访是确定的，并将获得关于癌症复发和存活的时间的数据。在这项建议的研究中，来自MECC研究的480例结直肠病例和20例正常粘膜将被选作蛋白质和基因表达分析，主要选择标准是在诊断时癌侵及肠壁的所有层，但没有远处转移(II和III期)。这项研究将包括同等数量的II期和III期患者，前者没有区域淋巴转移或延伸到邻近组织之外，而后者存在。第二期和第三期结肠癌的一个关键问题是确定预测癌症复发和死亡的特征。因此，我们研究的一个主要目标将是在480名患者中确定与癌症复发和死亡相关的基因和蛋白质标记物。此外，将在MECC研究中收集的大量临床、组织病理学和流行病学数据将使我们能够解决特定表达模式与特定临床和组织病理学特征以及饮食和环境因素的关系。

The NCI Director has challenged the scientific community to utilize existing and developing technologies to generate comprehensive profiles of molecular alterations in human tumors in order to define clinically relevant molecular tumor "signatures". In this project, we will pursue comprehensive studies of gene and protein expression in colorectal cancer. Colorectal cancer is a major cause of cancer morbidity and mortality in the western world, with about 140,000 new cases and 56,000 deaths annually in the U.S. Like other common epithelial cancers, its development is complex and a full accounting of its causes and pathogenesis remain elusive. The accumulation of mutations in proto- oncogenes and tumor suppresser genes contributes to the initiation of adenomatous lesions and their progression to carcinoma. In spite of the progress in cancer genetics, enormous work remains. An ongoing research project at the University of Michigan is entitled "Molecular Epidemiology of Colorectal Cancer (MECC)." The MECC project is a population-based, case-control study examining genetic sequence variation and environmental factors in colorectal cancer development. In this collaborative study, 2100 incident colorectal cases will be identified. In addition to collection of normal and tumor tissue, peripheral blood and serum are collected and stored on each case. Detailed histopathological studies are performed and epidemiologic risk factor information is obtained. Furthermore and of great importance for the work proposed here, clinical follow-up of patients entered into the MECC study is assured, and data on time to cancer recurrence and survival will be obtained. For the studies in this proposal, 480 colorectal cases and 20 normal mucosa specimens form the MECC study will be selected for the protein and gene expression analyses, with the principal selection criterion being that the cancer invaded through all layers of the bowel wall at the time of diagnosis, but distant metastases were absent (stages II and III). The study will include equal numbers of patients with stage II and III disease, where regional lymph node metastases or extension beyond contiguous tissues are absent in the former and present in the latter. A critical issue in stage II and III colon cancer is to define features which predict cancer recurrence and death. Therefore, a principal goal of our study will be to identify gene and protein markers which are associated with cancer recurrence and death in the 480 patients. In addition, the large body of clinical, histopathological, and epidemiological data to be collected in the MECC study will allow us to address the relationship of particular expression patterns to specific clinical and histopathological features as well as dietary and environmental factors.