Genome Wide Admixture Scan for Multiple Myeloma in African Americans

描述(申请人提供)：多发性骨髓瘤(MM)是一种由浆细胞的肿瘤克隆组成的恶性肿瘤，这种终末分化的B淋巴细胞负责产生抗体。在血液系统恶性肿瘤中，它是第二常见的死亡原因。尽管最近在治疗方面取得了进展，但5年存活率仍低于40%。非洲裔美国人的发病率比白人高2倍以上；发病率种族差异的原因尚不清楚。在有多发性骨髓瘤和/或其前驱症状--未确定意义的单克隆性伽马病(MGUS)家族史的人中，风险也增加了2-3倍。我们假设多发性骨髓瘤的风险有遗传因素，非裔美国人的部分额外风险是通过遗传变异来调节的。在这项应用中，我们建议进行全基因组关联研究，以确定导致非裔美国人多发性骨髓瘤风险的常见遗传变异。更具体地说，我们将检查2,072例非裔美国人多发性骨髓瘤病例和4,645名非裔美国人对照中的1,000,000个遗传标记。本研究将通过与NCI/SEER基于人口的癌症登记机构(加利福尼亚州、底特律、路易斯安那州和新泽西州)和6个非裔美国人人口众多地区的临床中心(阿拉巴马大学伯明翰分校、约翰·霍普金斯大学、埃默里大学、卡马诺斯癌症研究所/韦恩州立大学、西北大学、芝加哥大学和M.D.安德森癌症中心/德克萨斯大学)的合作网络来招募病例和收集样本。对照将包括来自美国各地的4645名健康的、未受影响的非裔美国人受试者。我们将通过关联测试1500例多发性骨髓瘤病例中的前100个SNP和来自美国和澳大利亚的多项现有研究中的3710个欧洲来源的对照，来评估我们研究结果的普适性。此外，我们将与NCI顾问兰德格伦博士一起，在700名患有MGUS的非裔美国人受试者和从NHANES招募的1400名对照中，检查风险变量与先兆MGUS的相关性。在这项提案中，我们将利用协作、大规模基因研究的优势，在经历这种癌症健康差异的人群(非裔美国人)中确定MM的共同风险等位基因。除了阐明非裔美国人多发性骨髓瘤的病因外，我们还希望发现可用于药物开发的新途径。我们的最终目标是减少非裔美国人因这种致命癌症而经历的健康差距。 公共卫生相关性：多发性骨髓瘤(MM)是一种血细胞(淋巴细胞)癌，5年存活率低于40%。这种癌症之所以重要，是因为它非常致命，而且它对服务不足的人群造成了不成比例的影响。由于未知的原因，非洲裔美国人患多发性骨髓瘤的风险是世界上最高的，而且受到影响的频率是美国白人的两倍多。在这项提案中，我们将与美国各地的其他机构合作，收集2072名非裔美国人多发性骨髓瘤患者的样本，并将他们的基因变异与4645名非裔美国人对照(具有先前的基因型别DNA)进行比较。除了阐明非裔美国人多发性骨髓瘤的病因外，我们还希望发现可用于药物开发的新途径。我们的最终目标是减少非裔美国人因这种致命癌症而经历的健康差距。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a malignancy consisting of a neoplastic clone of plasma cells, the terminally-differentiated B lymphocytes responsible for antibody production. It is the second most common cause of death among the hematological malignancies. Despite recent advances in treatment, the 5-year survival rate remains under 40%. African Americans experience incidence rates over 2-fold higher than those of Whites; the reasons for the racial differences in disease rates are unknown. Risk is also 2- to 3-fold elevated among persons with a family history of multiple myeloma and/or its precursor, monoclonal gammopathy of undetermined significance (MGUS). We hypothesize that there is a genetic component to multiple myeloma risk and that part of the excess risk in African Americans is mediated through inherited variation. In this application, we propose to perform a genome-wide association study to identify common genetic variants that contribute to multiple myeloma risk in the African American population. More specifically, we will examine 1,000,000 genetic markers in 2,072 African American multiple myeloma cases and 4,645 African American controls. Cases for this study will be recruited and specimens collected by means of a network of collaborations with NCI/SEER population-based cancer registries (California, Detroit, Louisiana and New Jersey) and clinical centers in 6 regions with large African-American populations (University of Alabama at Birmingham, Johns Hopkins University, Emory University, Karmanos Cancer Institute/Wayne State University, Northwestern University, University of Chicago, and M.D. Anderson Cancer Center/University of Texas). Controls will consist of 4,645 healthy unaffected African-American subjects from across the U.S. We will assess the generalizabilty of our findings by association testing of the top 100 SNPs in 1,500 MM cases and 3,710 controls of European origin in multiple existing studies from the U.S. and Australia. In addition, with NCI consultant Dr. Landgren, we will examine the associations of the risk variants with the precursor, MGUS among 700 African-American subjects with MGUS and 1,400 controls recruited from NHANES. In this proposal we will utilize the strengths of collaborative, large-scale genetic research to identify common risk alleles for MM in a population (African American) that experiences a health disparity with respect to this cancer. In addition to illuminating etiology of multiple myeloma in African Americans, we hope to discover new pathways that can be exploited for drug development. Our ultimate goal is to reduce the health disparity experienced by African Americans due to this fatal cancer. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) is a cancer of blood cells (lymphocytes) with a 5-year survival rate of under 40%. This cancer is important because it is highly fatal and because it disproportionately affects an underserved population. For unknown reasons, African Americans have among the highest risks of MM in the world and are affected more than twice as often as White Americans. In this proposal we will collaborate with other institutions across the U.S. to collect samples from 2,072 African American MM patients and compare their genetic variation to that of 4,645 African American controls (with previously genotyped DNA). In addition to illuminating the cause of multiple myeloma in African Americans, we hope to discover new pathways that can be used for drug development. Our ultimate goal is to reduce the health disparity experienced by African Americans due to this fatal cancer.