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

描述(由申请人提供)：这项探索性/发展性研究的目标是从表观基因组中鉴定与多发性骨髓瘤(MM)发病相关的DNA甲基化(DNaM)特征。假设dNaM图谱中的表观基因组改变与多发性骨髓瘤的风险改变有关，在多发性骨髓瘤患者中，dNaM基因的修改导致非裔美国人中观察到的额外风险。为了验证这一假设，我们打算(1)比较MM患者和对照的基因组甲基化(GWM)谱，使用Illumina甲基450K分析，使用按欧洲美国人和非裔美国人种族/民族分层的病例对照方法，(2)比较对MM重要的三种细胞类型的GWM谱，包括来自骨髓的CD138+骨髓瘤“肿瘤”细胞，来自骨髓微环境的内皮细胞和来自外周血的初级淋巴细胞，以及(3)使用仅病例方法比较欧美和非裔美国人MM病例之间的GWM谱。对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，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dNaM对MM风险的影响进行严格和全面的评估，这种影响在非裔美国人中不成比例地高。随着本申请中描述的实验关系的表征，我们将很好地促进生物标记物的发现，这些生物标记物可以以非侵入性和成本效益的方式应用于大量或处于风险中的人群。我们的方法提供了最好的机会来确定与MM的新的表观遗传学关系，并产生必要的初步数据，以研究功能基因组学作为一种工具，瞄准可能受益于个体化临床治疗或治疗干预的高危人群。 与公共健康相关：传统上，癌症被认为是由遗传异常引起的，例如导致肿瘤抑制基因丢失或致癌基因获得的突变，称为癌基因。表观遗传学是一门新学科，它将帮助我们理解遗传基因活动而不是基因突变是如何导致癌症的。这项研究的目的是确定导致非裔美国人多发性骨髓瘤负担不均的表观遗传因素。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，并更有效地治疗它。

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.