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: 8101206
• 负责人: PETER W LAIRD
• 金额: $ 49.44万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101206
• 关键词: Address; Age; Alcohol consumption; Anatomy; BRAF gene; Behavior; Benign; Candidate Disease Gene; Cell division; 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; Folate; Frequencies; Funding; Gender; Gene Mutation; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genome; 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 岛高甲基化。结直肠肿瘤的一个子集已被描述为具有异常大量的高甲基化 CpG 岛，从而定义了一种独特的表型，称为“CpG 岛甲基化表型”或“CIMP”。该提案的长期目标是使用通过结直肠癌研究合作家族登记处 (Colon CFR) 收集的结直肠癌样本来研究 CIMP 状态与分子、人口统计和组织病理学特征以及环境风险因素之间的关联。结直肠癌研究合作家族登记处 (Colon CFR) 是一个由 NCI 支持的联盟，旨在作为促进结直肠癌遗传流行病学合作和跨学科研究的资源。我们最近发布了改进的 DMA 甲基化标记集和分析技术，利用该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) 使用通过结肠 CFR 收集的 4,943 个基于人群的结直肠癌样本来估计 CIMP 状态与年龄、性别、家族史、种族和原籍国之间的关联，2) 估计 CIMP 状态与肿瘤位置、分级、浸润性边缘、淋巴细胞浸润、直接扩散、淋巴结扩散、静脉扩散和残留邻近息肉类型（如果存在）之间的关联，以及 3) 估计 CIMP 状态与选定危险因素（遗传和环境/生活方式因素）之间的关联，包括 BRAF 体细胞突变、MMR 基因种系突变、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。这项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变化。这些变化可以是结构性的，例如基因突变，也可以反映基因使用活跃程度的变化，称为表观遗传变化。这项研究将调查一些结直肠肿瘤如何获得异常大量的表观遗传变化，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。

项目成果

Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data.

• DOI: 10.1186/gb-2012-13-7-r61
• 发表时间: 2012-07-11
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Liu Y;Siegmund KD;Laird PW;Berman BP
• 通讯作者: Berman BP

Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer.

• DOI: 10.1371/journal.pone.0050266
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lange CP;Campan M;Hinoue T;Schmitz RF;van der Meulen-de Jong AE;Slingerland H;Kok PJ;van Dijk CM;Weisenberger DJ;Shen H;Tollenaar RA;Laird PW
• 通讯作者: Laird PW

Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains.

• DOI: 10.1038/ng.969
• 发表时间: 2011-11-27
• 期刊: Nature genetics
• 影响因子: 30.8