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

描述（由申请方提供）：本探索性/开发性研究的目的是从整个表观基因组中鉴定有助于多发性骨髓瘤（MM）发病机制的DNA甲基化（DNAm）谱。假设是DNAm谱中的表观基因组修饰与MM风险改变相关，并且在MM患者中，DNAm的修饰有助于在非裔美国人中观察到的过度风险。为了验证这一假设，我们打算（1）使用Illumina Methyl 450 K分析，使用按欧洲裔美国人和非洲裔美国人种族/种族分层的病例对照方法，比较MM病例和对照中来自人类基因组中> 450，000个CpG的全基因组甲基化（GWM）谱，（2）比较对MM重要的三种细胞类型中的GWM谱，包括来自骨髓的CD 138+骨髓瘤“肿瘤”细胞，骨髓微环境中的内皮细胞和外周血中的原代淋巴细胞（使用仅病例方法），以及（3）使用仅病例方法按细胞类型比较欧美和非裔美国MM病例的GWM特征。MM表型和相关风险因素的广泛表征，从现有的良好表征的人群，再加上全基因组的方法，利用我们的多学科研究团队的专业知识，将有助于严格和全面评估的影响DNAm对MM的风险是不成比例的非洲裔美国人。随着本申请中描述的实验关系的特征化，我们将做好准备以促进生物标志物的发现，其可以以非侵入性和具有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，以确定新的表观遗传学与MM的关系，并产生必要的初步数据，以调查功能基因组学作为一种工具，针对高危人群谁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.