Prognostic Molecular Markers of Colorectal Cancer

结直肠癌的预后分子标志物

基本信息

批准号：
7929935
负责人：
UPENDER MANNE
金额：
$ 8.59万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929935
关键词：
18q Admixture African African American Aggressive behavior Anatomic Sites Anatomy Apoptosis Apoptotic Biological Biological Markers Caucasians Caucasoid Race Cell Cycle Characteristics Clinical Colon Carcinoma Colorectal Adenocarcinoma Colorectal Cancer Colorectal Neoplasms Complex Confounding Factors (Epidemiology)Cyclin E DNA Data Data Set Databases Decision Making Diagnostic Neoplasm Staging Dinucleoside Phosphates Drug Formulations Epidemiology Ethnic Origin Ethnic group Evaluation Genes Goals Heterogeneity Histologic Human In Situ Nick-End Labeling Individual Investigation Knowledge Laboratories Location Loss of Heterozygosity MLH1 gene Malignant Neoplasms Microsatellite Instability Mismatch Repair Modeling Molecular Mucin-1 Staining Method Mutation Nuclear Oncogenes Oncologist Outcome Pathologic Patients Pattern Phenotype Poly A Population Study Prognostic Factor Prognostic Marker Publishing Race Site Staging Statistical Methods TP53 gene Techniques Therapeutic Intervention Thymidylate Synthase Tissue Microarray Tissues Tumor Suppressor Proteins Tumor stage Variant base caucasian American cyclooxygenase 2 data mining experience molecular marker novel novel marker outcome forecast patient population prognostic prognostic indicator racial and ethnic suppressin tool treatment response tumor

项目摘要

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.

该提案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志物的研究，但由于结果存在争议，尚未有新的标志物获得公认的临床实用性。最近，其他人和我们的实验室为解决一些争议而进行的研究表明，CRC 的几种分子和表型特征的预后价值随肿瘤的解剖位置和/或患者种族/民族而变化。因此，我们建议鉴定与肿瘤侵袭性相关的散发性结直肠癌的分子标志物，从而与非裔美国人和白种人患者的预后相关。由于对大量数据的综合评估需要强大的统计技术，因此我们建议使用知识发现工具来识别潜在有用的信息来预测患者的预后。在具体目标 1 中，将对 750 名非裔美国人和白种人的 CRC 患者群体进行分期和位点匹配的评估，以评估几个关键分子标志物的表型表达，这些分子标志物可能可以作为预测指标。免疫组织化学 (IHC) 分析的标记物为：DCC（结肠癌中缺失）、p53、p21waf-1、p27Kip-1、Mdm2、cyclin E、Ki67、Bcl-2、Bax、MUC1、环氧合酶 2 和胸苷酸合成酶。细胞凋亡的程度将利用TUNEL 来确定。在具体目标 2 中，将对从档案组织中提取的 DNA 进行 4 个 CA 二核苷酸 MS 位点（Mfd27、Mfd41、Mfd47 和 Mfd57）和 2 个多聚 A 重复序列（BAT25、BAT26）的微卫星不稳定性 (MSI) 分析。此外，还将评估组织阵列切片的 hMLH1 和 hMSH2 表达，以确定 DNA 错配修复缺陷的肿瘤。使用统计方法，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白种人的预后相关。在具体目标 3 中，我们将使用数据挖掘工具来识别具体目标 1 和 2 中生成的数据集中多个因素的复杂关系。最终，将为非裔美国人和白人结直肠癌患者开发单独的预后模型。这些研究的结果将帮助临床肿瘤学家使用 MSI 和表型模式识别侵袭性 CRC，并帮助选择潜在的治疗干预候选者。此外，这些策略可用于识别已生成的庞大分子流行病学数据库中的关键信息或决策知识发现。