CpG Island Methylator Phenotype in Human Colorectal Cancer

人类结直肠癌中的 CpG 岛甲基化表型

• 批准号: 7888132
• 负责人: PETER W LAIRD
• 金额: $ 51.15万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888132
• 关键词: Address; Age; Alcohol consumption; Anatomy; BRAF gene; Behavior; Benign; Candidate Disease Gene; Characteristics; Classification; Clinical; Colon; Colorectal Cancer; Colorectal Neoplasms; Cooperative Family Registry; Country; CpG Island Methylator Phenotype; CpG Islands; DNA; DNA Methylation; Defect; Detection; Diagnostic; Environmental Risk Factor; Enzymes; Epigenetic Process; Etiology; Family history of; Folate; Frequencies; Funding; Gender; Gene Mutation; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genome; Genus Cola; Germ-Line Mutation; Goals; Heterogeneity; Hormones; Human; Hypermethylation; Infiltration; Intake; Interdisciplinary Study; Knowledge; Location; Lymphocyte; Malignant - descriptor; Maps; Meat; Metabolic; Methodology; Methylation; Molecular; Mutation; Pathway interactions; Phenotype; Polyps; Prevalence; Publishing; Race; Recording of previous events; Reporting; Research Infrastructure; Research Personnel; Residual state; Resources; Risk Factors; Sampling; Smoking History; Somatic Mutation; Specimen; Standardization; Stretching; Study Subject; Technology; Tissues; Venous; base; cell growth; genetic epidemiology; genome wide association study; improved; lifestyle factors; lymph nodes; population based; promoter; sex; tool; tumor

DESCRIPTION (provided by applicant): Human colorectal cancer arises as a consequence of both genetic and epigenetic alterations, including promoter CpG island hypermethylation. A subset of colorectal tumors has been described to have an unusually high number of hypermethylated CpG islands, leading to the definition of a distinct phenotype, referred to as "CpG Island Methylator Phenotype", or "CIMP". The long-term objective of this proposal is to study the association between CIMP status and molecular, demographic, and histopathologic features, and environmental risk factors, using colorectal cancer samples collected through the Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR), an NCI-supported consortium intended as a resource to promote collaborative and interdisciplinary studies in the genetic epidemiology of colorectal cancer. We have recently published an improved DMA methylation marker set and analysis technology with which CIMP can be efficiently defined with high accuracy in archival colorectal cancer specimens. We propose to 1) estimate the association between CIMP status and age, sex, family history, race and country of origin, using 4,943 population-based colorectal cancer samples collected through the Colon CFR, 2) estimate the association between CIMP status and tumor location, grade, invasive margin, lymphocytic infiltration, direct spread, lymph node spread, venous spread and type of residual adjacent polyp, if present, and 3) estimate the association between CIMP status and selected risk factors, both genetic and environmental/lifestyle factors, including somatic mutations in BRAF, germline mutations in the MMR genes, smoking history, red meat and alcohol intakes, dietary folate intake, folate metabolic enzyme polymorphisms and history of hormone use. This study will contribute to our understanding of the etiology of CIMP, and its relationship to other molecular and histopathologic features of colorectal cancer. Colorectal cancer involves changes to genes that control cell growth and division. These changes can be structural, as in the case of genetic mutations, or they can reflect an alteration in how actively the gene is being used, referred to as an epigenetic change. This study will investigate how some colorectal tumors acquire an unusually high number of epigenetic changes, with the long-term goal of using this knowledge to block or reverse these types of deleterious changes.

描述（由申请人提供）：人类结直肠癌是遗传和表观遗传改变的结果，包括启动子CpG岛超甲基化。结直肠肿瘤的一个子集被描述为具有异常高数量的高甲基化CpG岛，导致一种独特表型的定义，称为“CpG岛甲基化表型”或“CIMP”。该提案的长期目标是研究CIMP状态与分子、人口统计学、组织病理学特征和环境危险因素之间的关系，使用通过结肠直肠癌研究合作家庭登记处（Colon CFR）收集的结直肠癌样本，该协会是nci支持的一个联盟，旨在促进结直肠癌遗传流行病学的合作和跨学科研究。我们最近发表了一种改进的DMA甲基化标记集和分析技术，可以在档案结直肠癌标本中高效、高精度地定义CIMP。我们建议1)估计CIMP状态与年龄、性别、家族史、种族和原产国之间的关系，使用通过结肠CFR收集的4,943例基于人群的结直肠癌样本；2)估计CIMP状态与肿瘤位置、分级、浸润边缘、淋巴细胞浸润、直接扩散、淋巴结扩散、静脉扩散和残余邻近息肉类型之间的关系，如果存在的话。3)评估CIMP状态与选择的危险因素之间的关系，包括遗传和环境/生活方式因素，包括BRAF的体细胞突变、MMR基因的种系突变、吸烟史、红肉和酒精摄入量、膳食叶酸摄入量、叶酸代谢酶多态性和激素使用史。本研究将有助于我们了解CIMP的病因及其与结直肠癌其他分子和组织病理学特征的关系。结直肠癌涉及控制细胞生长和分裂的基因的改变。这些变化可以是结构性的，就像基因突变的情况一样，或者它们可以反映基因被使用的活跃程度的变化，称为表观遗传变化。本研究将探讨一些结直肠肿瘤是如何获得异常高数量的表观遗传变化的，其长期目标是利用这些知识来阻止或逆转这些类型的有害变化。