A genome-wide methylation study of epigenetic contributions to multiple myeloma

多发性骨髓瘤表观遗传贡献的全基因组甲基化研究

基本信息

批准号：
8192004
负责人：
Elizabeth E Brown
金额：
$ 12.75万
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：
2011
资助国家：
美国
起止时间：
2011-07-07 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8192004
关键词：
Accounting Affect African American American Apoptosis Biological Markers Bone Marrow Bone Marrow Cells Cancer Etiology Candidate Disease Gene Cell Death Process Clinical Management Coupled DNA DNA Methylation DNA Sequence Data Discipline ENG gene Endothelial Cells Ensure Epigenetic Process Ethnic Origin Etiology European Evaluation Exploratory/Developmental Grant Family Study Funding Gene Mutation Genes Genetic Genome Goals Human Genome Incidence Inherited Knowledge Lead Lymphocyte Malignant Neoplasms Methylation Modeling Modification Molecular Abnormality Monoclonal gammopathy of uncertain significance Multiple Myeloma Mutation Oncogenes PECAM1 gene Pathogenesis Patients Peripheral Blood Lymphocyte Persons Phenotype Plasma Plasma Cells Population Populations at Risk Premalignant Public Health Race Research Resistance Risk Risk Factors Site Specific qualifier value Testing Therapeutic Intervention Time Tissues Tumor Suppressor Genes base cancer cell case control cell type cost effective epigenomics functional genomics genome sequencing genome-wide high risk innovation insight meetings multidisciplinary neoplastic cell novel peripheral blood racial difference sex tool tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The goal of this Exploratory/Developmental study is to identify DNA methylation (DNAm) profiles from across the epigenome that contribute to multiple myeloma (MM) pathogenesis. The hypothesis is that epigenomic modification in DNAm profiles is associated with altered risk of MM and among patients with MM, modifications in DNAm contribute to the excess risk observed among African Americans. To test this hypothesis, we intend to (1) compare genome-wide methylation (GWM) profiles in MM cases and controls from >450,000 CpGs in the human genome, using the Illumina Methyl450K analysis using a case-control approach stratified by European American and African American race/ethnicity, (2) compare GWM profiles in three cell types important for MM including CD138+ myeloma "tumor" cells from the bone marrow, endothelial cells from the bone marrow microenvironment and primary lymphocytes from the peripheral blood using a case-only approach and (3) compare GWM profiles between European American and African American cases of MM by cell type using a case-only approach. The extensive characterization of the MM phenotype and related risk factors from existing well-characterized populations coupled with a genome-wide approach that capitalizes on the expertise of our multidisciplinary investigative team will facilitate a rigorous and comprehensive evaluation of the effect of DNAm on MM risk that is disproportionately higher among African Americans. As the experimental relationships described in this application are characterized, we will be well-poised to facilitate biomarker discovery that can be applied to large or at-risk populations in a non-invasive and cost-effective manner. Our approach offers the best opportunity to identify novel epigenetic relationships with MM and to generate preliminary data necessary to investigate functional genomics as a tool for targeting high-risk populations who may benefit from individualized clinical management or therapeutic intervention. PUBLIC HEALTH RELEVANCE: Traditionally cancer was thought to result from genetic abnormalities such as mutations that lead to a loss of tumor suppressor genes or a gain of cancer causing genes, called oncogenes. Epigenetics is a new discipline that will help us to understand how inherited gene activity instead of genetic mutations contributes to cancer. The purpose of this study is to identify epigenetic factors that contribute to the unequal burden of multiple myeloma in African Americans. The knowledge gained from this study may help us to lower the risk of multiple myeloma and treat it more effectively.

描述（由申请人提供）：这项探索性/发育研究的目的是确定来自表观基因组的DNA甲基化（DNAM）特征，从而有助于多发性骨髓瘤（MM）发病机理。假设是，DNAM概况中的表观基因组修饰与MM和MM患者的风险改变有关，DNAM的修改会导致非裔美国人观察到的过量风险。为了检验这一假设，我们打算（1）使用Illumina甲基450k分析使用欧洲和非洲人种族/民族的cy-efiles（2）在人类基因组中比较人类基因组中> 450,000 cpG的对照中的全基因组甲基化（GWM）谱，并比较> 450,000 cpG的对照。从骨髓中，使用仅病例方法的骨髓微环境中的内皮细胞和外周血的原代淋巴细胞，（3）通过使用病例方法通过细胞类型进行欧美和非裔美国人MM病例的GWM谱。现有特征良好的人群的MM表型和相关风险因素的广泛表征，再加上全基因组的方法，该方法利用了我们的多学科研究团队的专业知识，将促进对DNAM对MM风险的影响的严格和全面评估，而MM对MM风险的影响不成比例地较高。正如本应用程序中描述的实验关系所表征的那样，我们将得到充分的精力，以促进生物标志物发现，该发现可以以无创和成本效益的方式应用于大型或处于危险中的人群。我们的方法为确定与MM的新表观遗传关系提供了最佳机会，并生成必要的初步数据，以研究功能基因组学作为靶向可能受益于个性化临床管理或治疗干预措施的高风险人群的工具。公共卫生相关性：传统上，癌症被认为是遗传异常引起的，例如导致肿瘤抑制基因丧失的突变或引起癌症的癌症的增加，称为致癌基因。表观遗传学是一门新学科，它将帮助我们了解遗传性基因活性是如何有助于癌症的。这项研究的目的是确定导致非裔美国人多发性骨髓瘤不平等负担的表观遗传因素。从这项研究中获得的知识可能有助于我们降低多发性骨髓瘤的风险并更有效地对待。