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: 8082654
• 负责人: NICOLA J. CAMP
• 金额: $ 18.92万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082654
• 关键词: Accounting; Address; Age; B-Lymphocytes; Biological Markers; Bone Marrow; Cessation of life; Chromosome Mapping; Clinical; Clinical Treatment; 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（由申请人提供）：多发性骨髓瘤（MM）是一种血液恶性肿瘤。它是一种浆细胞癌，其特征是骨髓中恶性浆细胞的积累和单克隆免疫球蛋白的增加。它占所有癌症的1%，通常无法治愈，中位生存期约为4年。它约占血液恶性肿瘤死亡人数的20%，占所有癌症死亡人数的2%。最近的研究表明，MM的发病率可能正在增加，并且发生在更早的年龄。MM的病因不明；然而遗传因素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异。对于人群归因风险而言，大效应量的罕见风险变异可能相对不显著，但与确定携带此类变异的个体具有直接相关性。发现一种罕见的MM风险变异将立即产生临床影响。这个建议将集中于绘制这些罕见的变异。我们描述了一种高风险谱系设计和一种新的分析技术，这种技术是专门开发的，具有很好的检测罕见风险变异的能力。相比之下，流行的病例-对照关联设计几乎没有作用。因此，我们的研究对该领域是有利的，并且对其他正在进行的定位MM常见变体的努力是高度补充的，因为它扩大了可能被识别的变体类型的范围。我们将使用独特而强大的犹他州人口数据库（UPDB），该数据库汇集了基于人群的家谱和癌症登记数据，以确定扩展的高风险MM谱系进行研究。我们将使用我们新的共享基因组片段方法进行分析。这一分析只考虑了抽样的、远亲的MM病例，并提出了一个问题，即是否有任何共享的基因组片段的长度比偶然预期的要长。从理论上讲，远亲之间的机会共享是极不可能的。在MM病例之间至少有15个减数分裂的高风险家系有能力识别全基因组具有统计学意义的共享。因此，这些区域是罕见风险变异的良好候选者。虽然我们相信我们的初步研究清楚地表明，这种方法具有极好的潜力，但我们绘制MM风险变体的创新方法是高风险的，因为以前没有尝试过。如果成功，该提议的高回报是显而易见的，无论是在MM的基因定位方面，还是在证明我们的新方法在基因发现中一般发挥有价值的作用方面。本建议的直接目标是定位MM的罕见风险变量。最终目标将是识别具体的风险变量。这些发现的影响将是巨大的，并将导致在治疗和控制这一致命疾病方面取得重大进展。特别是，即使是鉴定一种罕见的、对MM具有大效应量的遗传生物标志物，也将是MM病因学中重要而关键的发现，并可能对检测和诊断具有直接的临床意义。