Novel molecular signatures of colorectal cancer

结直肠癌的新分子特征

• 批准号: 8123844
• 负责人: Victoria Valinluck Lao
• 金额: $ 5.47万
• 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 2015-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123844
• 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; epigenomics; genome-wide; inhibitor/antagonist; insight; 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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is a leading cause of cancer related deaths in the United States. Considerable heterogeneity exists among the clinical behavior of colorectal cancers, particularly regarding response to medical treatment, highlighting the need for more accurate markers of survival and disease recurrence. The studies proposed here will identify genes that have the potential for directing the development of novel biomarkers and more effective therapeutic strategies for patients with colorectal cancers.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症相关死亡的主要原因。它通过结肠上皮细胞中遗传和表观遗传改变的积累驱动的多步骤过程发展，导致转化为癌细胞。表观遗传改变在结直肠癌中的作用尚不完全清楚。结直肠癌中成百上千个基因发生异常甲基化，但大多数这些事件的生物学意义尚不清楚。异常 DNA 甲基化可能导致失活的基因包括信号通路中的基因，以及调节增殖和凋亡的基因，例如 RET 条件肿瘤抑制因子等。受表观遗传改变影响的基因的生物学功能表明它们可能有助于预测生物学和临床肿瘤行为。 CRC 的临床行为存在相当大的异质性，突出表明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预测对治疗的反应和临床结果，而与临床病理阶段无关，这是目前最好的预测因素。由于结直肠癌的表观遗传改变影响肿瘤的生物学和临床行为，了解这些变化可以产生用于结直肠癌预后和治疗的生物标志物。 本研究提出的三个目标将描述结直肠癌全基因组表观遗传改变的特征，并将这些表观遗传变化与蛋白质表达和生物学功能相关联。目标 1 将确定新型甲基化基因 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 可以诱导携带甲基化 RET 的 CRC 细胞系中的 RET 表达。基因重组研究将研究 RET 甲基化对细胞凋亡和细胞增殖的影响，以及对选定细胞信号通路激活状态的影响。目标 2 将对具有临床不同行为的结直肠癌分子亚型进行全面的表观基因组表征：微卫星不稳定 (MSI)、微卫星稳定 (MSS) 和 CpG 岛甲基化表型 (CIMP) 肿瘤。将确定原代 CRC 和细胞系的分子亚群，并使用 DNA 甲基化阵列表征其甲基化状态。目标 3 将与目标 2 平行，利用抗体阵列确定细胞系和原发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目标 2 中的甲基化组表征进行比较，以确定哪些基因在 CRC 中被沉默，以及甲基化变化会发生哪些相关的蛋白质组变化。这些研究将为识别和开发生物标志物提供关键信息，从而更有效地治疗结直肠癌患者。 公共卫生相关性：结直肠癌是美国癌症相关死亡的主要原因。结直肠癌的临床行为存在相当大的异质性，特别是在对药物治疗的反应方面，突出表明需要更准确的生存和疾病复发标记。这里提出的研究将确定有潜力指导新型生物标志物开发和结直肠癌患者更有效治疗策略的基因。