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

描述（由申请人提供）：本探索性/发展性研究的目标是确定与多发性骨髓瘤（MM）发病机制有关的表观基因组中的DNA甲基化（DNAm）谱。假设是DNAm谱的表观基因组修饰与MM的风险改变有关，并且在MM患者中，DNAm的修饰导致非裔美国人观察到的风险增加。为了验证这一假设，我们打算(1)使用Illumina甲基化450k分析方法，采用欧美和非裔美国人种族/民族分层的病例对照方法，比较来自人类基因组中bbbb45万个CpGs的MM病例和对照组的全基因组甲基化（GWM）谱；(2)比较三种对MM重要的细胞类型的GWM谱，包括来自骨髓的CD138+骨髓瘤“肿瘤”细胞；(3)采用病例法，按细胞类型比较欧美和非裔美国MM病例间的GWM特征。通过对现有人群的MM表型和相关风险因素的广泛表征，再加上利用我们多学科调查团队的专业知识的全基因组方法，将有助于对非裔美国人中不成比例更高的DNAm对MM风险的影响进行严格和全面的评估。由于本应用程序中描述的实验关系具有特征，我们将很好地准备促进生物标志物的发现，可以以非侵入性和成本效益的方式应用于大型或高危人群。我们的方法提供了最好的机会来确定与MM的新的表观遗传关系，并产生必要的初步数据，以研究功能基因组学作为针对高危人群的工具，这些高危人群可能受益于个性化的临床管理或治疗干预。

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.