Shared Genomic Segment Analysis for Localizing Multiple Myeloma Genes

用于定位多发性骨髓瘤基因的共享基因组片段分析

• 批准号: 7963659
• 负责人: NICOLA J. CAMP
• 金额: $ 16.37万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963659
• 关键词: Accounting; Address; Age; B-Lymphocytes; Biological Markers; Bone Marrow; Cessation of life; Chromosome Mapping; Clinical; Clinical assessments; Data; Detection; Development; Diagnosis; Disease; Distant; Early Diagnosis; Etiology; Family; Genealogy; Genes; Genetic; Genetic Predisposition to Disease; Genetic screening method; Genomic Segment; Goals; Hematologic Neoplasms; Immunoglobulins; Incidence; Individual; Informed Consent; Intervention; Knowledge; Lead; Length; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Maps; Medical Records; Meiosis; Methods; Multiple Myeloma; Participant; Plasma Cells; Play; Population Attributable Risks; Population Database; Prevention; Production; Public Health; Recording of previous events; Relative (related person); Research Design; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Statistical Methods; Susceptibility Gene; Techniques; Utah; Variant; base; case control; clinically relevant; conventional therapy; density; design; genetic epidemiology; genetic pedigree; genetic risk factor; genome-wide; high risk; innovation; member; neoplasm registry; novel; novel strategies; population based; public health relevance

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a hematologic malignancy. It is a cancer of the plasma cells characterized by the accumulation of malignant plasma cells in the bone marrow and increased production of a monoclonal immunoglobulin. It represents 1% of all cancers and is usually incurable with a median survival of about four years. It accounts for approximately 20% of deaths from hematologic malignancies and 2% of deaths from all cancers. Recent studies indicate that MM may be increasing in incidence and occurring at earlier ages. The etiology of MM is unclear; however evidence for a genetic component is compelling. In particular, there is strong evidence to suggest the existence of rare risk variants. Rare risk variants of large effect size may be relatively insignificant with regard to population attributable risk, but have immediate relevance for individuals identified to carry such variants. The discovery of a single rare risk variant for MM would provide immediate clinical impact. This proposal will focus on mapping these rare variants. We describe a high-risk pedigree design and a novel analysis technique that is specifically developed and has good power to detect rare risk variants. In contrast, the popular case-control association design has little or no power. Our study will therefore be advantageous to the field, and is highly complementary to other on-going efforts to localize common variants for MM, because it broadens the scope of the types of variants that may be identified. We will use the unique and powerful Utah Population Database (UPDB) that brings together population-based genealogical and cancer registry data to identify extended high-risk MM pedigrees to study. We will use our novel shared genomic segment method for analysis. This analysis considers only sampled, distantly related MM cases and poses the question as to whether the length of any shared genomic segment is longer than expected by chance. Theoretically, chance sharing in distant relatives is extremely improbable. High-risk pedigrees with at least 15 meioses between MM cases have the capacity for identifying genome wide statistically significant sharing. These regions are therefore good candidates for harboring rare risk variants. Our innovative approach to mapping risk variants for MM is high-risk because it has not been attempted previously, although we believe our preliminary studies clearly indicate that this approach has excellent potential. If successful, the high pay-off of the proposal is evident both in terms of gene localization for MM and in the proof-of-principal that our novel approach has a valuable role to play in gene finding in general. The immediate goal of this proposal is to localize rare risk variants for MM. The ultimate goal will be to identify the specific risk variants. The impact of such discoveries will be high and will lead to significant advances in treatment and control of this fatal disease. In particular, the identification of even a single rare, genetic biomarker with large effect size for MM, will be an important and critical discovery in the etiology of MM and could have immediate clinical relevance for detection and diagnosis. PUBLIC HEALTH RELEVANCE: This project will use novel methods to localize rare genetic biomarkers for multiple myeloma. If successful, the clinical implication for at-risk individuals in high-risk pedigrees would be the early detection and diagnosis of multiple myeloma. Knowledge of genetic risk factors is informative in general for increasing our understanding of disease etiology. Ultimately, the potential public health implications are significant improvements in detection, diagnosis, intervention, treatment and prevention of MM.

描述（由申请方提供）：多发性骨髓瘤（MM）是一种血液恶性肿瘤。它是一种浆细胞癌，其特征是恶性浆细胞在骨髓中的积聚和单克隆免疫球蛋白的产生增加。它占所有癌症的1%，通常无法治愈，中位生存期约为4年。它占血液恶性肿瘤死亡的约20%，占所有癌症死亡的2%。最近的研究表明，MM的发病率可能会增加，并发生在较早的年龄。MM的病因尚不清楚;然而，遗传成分的证据是令人信服的。特别是，有强有力的证据表明存在罕见的风险变体。大效应量的罕见风险变异对于人群归因风险可能相对不显著，但对于经鉴定携带此类变异的个体具有直接相关性。MM单一罕见风险变异的发现将立即产生临床影响。这项提案将集中在绘制这些罕见的变异。我们描述了一个高风险的系谱设计和一种新的分析技术，是专门开发的，并具有良好的权力，以检测罕见的风险变异。相比之下，流行的病例对照关联设计几乎没有或没有权力。因此，我们的研究将有利于该领域，并与其他正在进行的MM常见变异定位工作高度互补，因为它扩大了可能识别的变异类型的范围。我们将使用独特而强大的犹他州人口数据库（UTB），该数据库汇集了基于人口的系谱和癌症登记数据，以确定扩展的高风险MM家系进行研究。我们将使用我们新的共享基因组片段方法进行分析。该分析仅考虑了采样的、远亲的MM病例，并提出了关于任何共享基因组片段的长度是否偶然长于预期的问题。从理论上讲，远房亲戚的机会分享是极不可能的。在MM病例之间具有至少15个减数分裂的高风险谱系具有鉴定全基因组统计学显著共享的能力。因此，这些区域是隐藏罕见风险变体的良好候选者。我们绘制MM风险变异的创新方法是高风险的，因为以前没有尝试过，尽管我们相信我们的初步研究清楚地表明这种方法具有很好的潜力。如果成功的话，该提案的高回报在MM的基因定位方面以及我们的新方法在基因发现中发挥重要作用的原理证明方面都是显而易见的。本提案的近期目标是将MM的罕见风险变体本地化。最终目标是识别特定的风险变体。这些发现的影响将很大，并将导致这种致命疾病的治疗和控制取得重大进展。特别是，即使是一个罕见的，遗传生物标志物与MM的大效应量的鉴定，将是一个重要的和关键的发现MM的病因，并可能有直接的临床意义的检测和诊断。 公共卫生相关性：该项目将使用新方法定位多发性骨髓瘤的罕见遗传生物标志物。如果成功的话，对高危家系中高危个体的临床意义将是多发性骨髓瘤的早期检测和诊断。遗传危险因素的知识是信息一般增加我们对疾病病因的理解。最终，潜在的公共卫生影响是在MM的检测、诊断、干预、治疗和预防方面的重大改进。