Prognostic Molecular Markers of Colorectal Cancer

这项建议的总体目标是确定结直肠腺癌(CRC)的潜在预后标志物。尽管发表了大量关于结直肠癌预后标记物的研究，但由于有争议的结果，还没有新的标记物达到公认的临床实用价值。最近来自其他实验室和我们实验室的一些解决争议的研究表明，癌细胞的几个分子和表型特征的预后价值随着肿瘤的解剖位置和/或患者的种族/民族而不同。因此，我们建议确定与非裔美国人和高加索人患者的肿瘤侵袭性和预后相关的散发性癌的分子标志物。由于对海量数据的综合评估需要强大的统计技术，我们建议使用知识发现工具来识别潜在的有用信息，以预测患者的预后。在具体目标1中，将评估非洲裔美国人和高加索人各750名分期和地点匹配的结直肠癌患者群体的几个关键分子标志物的表型表达，这些标志物可能是可接受的预后指标。免疫组织化学分析的标志物有：DCC(在结肠癌中缺失)、P53、p21waf-1、p27Kip-1、MDM2、Cyclin E、Ki67、Bcl2、Bax、MUC1、环氧合酶2和胸苷酸合酶。用TUNEL法测定细胞凋亡的程度。在具体目标2中，将分析从档案组织中提取的DNA在4个CA-二核苷酸MS基因座(Mfd27、Mfd41、Mfd47和Mfd57)和2个PolyA重复序列(BAT25、BAT26)上的微卫星不稳定性(MSI)。此外，组织阵列切片将评估hMLH1和hMSH2的表达，以确定DNA错配修复缺陷肿瘤。根据肿瘤的解剖位置，表型变异和MSI水平将与非裔美国人和高加索人的预后相关。在具体目标3中，我们将使用数据挖掘工具来识别在具体目标1和2中产生的数据集中多种因素的复杂关系。最终，将为患有结直肠癌的非裔美国人和白人患者开发不同的预后模型。这些研究的结果将有助于临床肿瘤学家使用MSI和表型模式识别侵袭性形式的CRC，并有助于选择潜在的治疗干预方案。此外，这些策略可用于识别已生成的大量分子流行病学数据库中的关键信息或决策知识发现。

The overall goal of this proposal is to identify potential prognostic markers of colorectal adenocarcinoma (CRC). Despite numerous published studies on prognostic markers of CRC, no new marker has achieved accepted clinical utility due to controversial results. Recent studies to resolve some of the controversies, from the laboratories of others and ours, have suggested that prognostic value of several molecular and phenotypic features of CRCs vary with anatomic location of the tumor and/or with patient race/ethnicity. Therefore, we propose to identify the molecular markers of sporadic CRCs that are associated with aggressiveness of the tumor hence prognosis of African-American and Caucasian patients. Since the comprehensive evaluation of vast amounts of data requires powerful statistical techniques, we propose to use knowledge discovery tools to identify potentially useful information to predict patient prognosis. In Specific Aim 1, stage-and site-matched 750 CRC patient populations each, of African-Americans and Caucasians will be evaluated for phenotypic expression of several key molecular markers which are likely to be acceptable as prognosticators. The markers to be analyzed immunohistochemically (IHC) are: DCC (deleted in colon cancer), p53, p21waf-1, p27Kip-1, Mdm2, cyclin E, Ki67, Bcl-2, Bax, MUC1, cyclooxygenase 2, and thymidylate synthase. The extent of apoptosis will be determined utilizing TUNEL. In Specific Aim 2, DNA extracted from archival tissues will be analyzed for microsatellite instability (MSI) at 4 CA-dinucleotide MS loci (Mfd27, Mfd41, Mfd47, and Mfd57) and 2 poly-A repeats (BAT25, BAT26). In addition, the tissue array sections will be evaluated for the expression of hMLH1 and hMSH2 to determine DNA mismatch repair deficient tumors. The phenotypic variations and the level of MSI will be correlated with the prognosis of African-Americans and Caucasians based on the anatomic location of the tumor using statistical methods. In Specific Aim 3, we will use data mining tools to identify the complex relationships of multiple factors in data sets generated in Specific Aims 1 and 2. Eventually, separate prognostic models will be developed for African-American and Caucasian patients with CRC. The findings of these studies will aid the clinical oncologist in identifying aggressive forms of CRCs using MSI and phenotypic patterns, and help in selecting potential candidates for therapeutic interventions. Additionally, these strategies can be used to identify key information or decision making knowledge discoveries in vast molecular epidemiological databases that are already generated.