Novel molecular signatures of colorectal cancer

结直肠癌的新分子特征

• 批准号: 8413128
• 负责人: Victoria Valinluck Lao
• 金额: $ 1.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-25 至 2013-06-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413128
• 关键词: Aberrant DNA Methylation; Affect; Antibodies; Apoptosis; Behavior; Biological; Biological Markers; Biological Process; CDKN2A gene; Cancer Etiology; Cancer cell line; Candidate Disease Gene; Cell Line; Cell Proliferation; Cells; Cessation of life; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; CpG Island Methylator Phenotype; CpG Islands; DNA Methylation; Data Set; Development; Disease; Epigenetic Process; Epithelial Cells; Epithelium; Event; Gene Mutation; Gene Silencing; Genes; Genetic; Heterogeneity; Lead; MGMT gene; MLH1 gene; Malignant Neoplasms; Medical; Methylation; Microsatellite Repeats; Molecular; Molecular Profiling; Normal Cell; Outcome; Patients; Predictive Factor; Primary Neoplasm; Process; Proteins; Proteome; Proteomics; RET gene; Recurrence; Role; Running; Sampling; Signal Pathway; Signal Transduction; Staging; Subgroup; The Cancer Genome Atlas; Therapeutic; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; adenoma; base; cancer cell; effective therapy; epigenome; epigenomics; genome-wide; inhibitor/antagonist; insight; methylome; novel; outcome forecast; promoter; protein expression; reconstitution; repository; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a leading cause of cancer related death in the United States. It develops through a multistep process driven by the accumulation of genetic and epigenetic alterations in colonic epithelial cells leading to transformation into cancer cells. The role of epigenetic alterations in CRC is incompletely understood. Hundreds to thousands of genes are aberrantly methylated in CRC, yet the biological significance of most of these events is unknown. The genes that can be inactivated by aberrant DNA methylation include genes in signaling pathways, and those that regulate proliferation and apoptosis, such as the RET conditional tumor suppressor among many others. The biological functions of the genes that are affected by epigenetic alterations suggest that they may be useful for predicting the biological and clinical tumor behavior. Considerable heterogeneity exists among the clinical behavior of CRCs, highlighting the need for more accurate markers of survival and disease recurrence. Studies to date suggest that both genetic and epigenetic alterations can predict response to therapy and clinical outcome independently of clinicopathologic stage, currently the best predictive factor. As epigenetic alterations in CRC affect the biological and clinical behavior of the tumors, understanding these changes can lead to biomarkers for prognosis and treatment of CRC. The three aims proposed in this study will characterize genome-wide epigenetic alterations in CRC and correlate these epigenetic changes with protein expression and biological function. Aim 1 will determine the role of a novel methylated gene, RET, on cell signaling and colon cancer progression. RET expression in CRC cell lines that carry methylated RET will be induced using the DNMT inhibitor, DAC. Gene reconstitution studies will investigate the effects of RET methylation on apoptosis and cell proliferation, as well as on the activation state of select cell signaling pathways. Aim 2 will perform a comprehensive epigenomic characterization of colorectal cancer molecular subtypes with clinically distinct behaviors: Microsatellite Unstable (MSI), Microsatellite stable (MSS) and CpG Island Methylator Phenotype (CIMP) tumors. The molecular subgroup of primary CRC and cell lines will be determined, and their methylation status characterized using DNA methylation arrays. Aim 3 will parallel Aim 2 and determine the proteome of colorectal cancer molecular subtypes in cell lines and primary tumor using antibody arrays. Results of the proteome characterization will be compared to the methylome characterization in Aim 2 to determine which genes are silenced in CRC and what associated proteomic changes occur with the methylation changes. These studies will provide critical information for identifying and developing biomarkers for more effective treatment of people with CRC.

描述（由申请人提供）：大肠癌（CRC）是美国与癌症有关的主要原因。它通过由结肠上皮细胞中遗传和表观遗传学改变的积累驱动的多步过程发展，从而导致转化为癌细胞。表观遗传改变在CRC中的作用尚不完全理解。在CRC中，数百至成千上万的基因被异常甲基化，但是大多数这些事件的生物学意义尚不清楚。可能被异常DNA甲基化灭活的基因包括信号传导途径中的基因，以及调节增殖和凋亡的基因，例如RET条件抑制抑制剂。受表观遗传学改变影响的基因的生物学功能表明，它们可能对预测生物学和临床肿瘤行为有用。 CRC的临床行为之间存在相当大的异质性，这突出了需要更准确的生存和疾病复发标记。迄今为止的研究表明，遗传和表观遗传改变都可以独立于临床病理阶段（目前是最佳预测因素）来预测对治疗和临床结果的反应。由于CRC的表观遗传改变会影响肿瘤的生物学和临床行为，因此了解这些变化可能会导致预后和治疗CRC的生物标志物。 本研究提出的三个目标将表征CRC中全基因组的表观遗传学改变，并将这些表观遗传学变化与蛋白质表达和生物学功能相关联。 AIM 1将确定一种新型甲基化基因，RET在细胞信号传导和结肠癌进展中的作用。使用DNMT抑制剂DAC诱导携带甲基化RET的CRC细胞系中的RET表达。基因重建研究将研究RET甲基化对细胞凋亡和细胞增殖的影响，以及选择细胞信号通路的激活状态。 AIM 2将对具有临床上不同行为的结直肠癌分子亚型进行全面的表观分析：微卫星不稳定（MSI），微卫星稳定（MSS）和CPG岛甲基甲基表型（CIMP）肿瘤。将确定原代CRC和细胞系的分子亚组，并使用DNA甲基化阵列来表征其甲基化状态。 AIM 3将平行AIM 2，并使用抗体阵列确定细胞系和原发性肿瘤中结直肠癌分子亚型的蛋白质组。蛋白质组表征的结果将与AIM 2中的甲基表征进行比较，以确定哪些基因在CRC中被沉默，以及甲基化变化发生的哪些相关蛋白质组学变化。这些研究将为识别和开发生物标志物提供关键信息，以对CRC患者进行更有效的治疗。