Influence of germ line genetic variation on myeloma progression and survival

种系遗传变异对骨髓瘤进展和生存的影响

基本信息

批准号：
8814844
负责人：
CELINE M VACHON
金额：
$ 23.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814844
关键词：
13q 17p Accounting Affect Age Alleles Amino Acid Substitution Biological Biological Markers Bone Marrow Breast Calcium Cell Line Cell Proliferation Centrosome Cessation of life Characteristics Chromosome abnormality Clinical Code Collaborations Cytogenetics Data Data Set Diagnosis Disease Esophageal Evaluation Future Gene Expression Gene Expression Profile Genes Genetic Genetic Variation Genotype Germ Lines Grant Haplotypes Health Hematologic Neoplasms Hemoglobin Inherited Lytic Lesion Malignant Neoplasms Malignant neoplasm of lung Modeling Multiple Myeloma Nature Pancreas Pathway interactions Patients Plasma Cells Population Predisposition Prognostic Factor Renal function Research Personnel S-Phase Fraction Serum Single Nucleotide Polymorphism Staging Subfamily lentivirinae Testing Therapeutic Transfection United States Untranslated RNA Variant base bone clinical predictors cohort follow-up genetic association genetic variant genome wide association study genome-wide hazard high risk high throughput screening improved in vitro Model indexing innovation multicatalytic endopeptidase complex novel outcome forecast predictive modeling prognostic prognostic value rare variant research study response risk variant targeted treatment trait tumor

项目摘要

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is considered a heterogeneous disease with substantial variation in response to therapy and survival among different patients. A variety of biomarkers exist that can help predict MM prognosis including cytogenetic markers and gene expression signatures. MM is known to be a partially heritable trait and recent genome wide association studies (GWAS) have identified eight SNPs that are associated with MM susceptibility. However, it is unknown whether germ line variants may also affect MM survival. We used a genome wide association (GWAS) approach to determine whether there are any germ line genetic variants that may affect survival among 592 MM patients. We identified a genome-wide significant association with a locus on 16p13 (p=2.8x10-10). The finding was replicated in a separate cohort of 772 patients. This proposal will seek to expand on these findings. We have formed a consortium of investigators with studies of multiple myeloma including over 3000 patients with data on survival. First, we will investigate the effect of the genotypes discovered by GWAS in the context of other clinical predictors of survival and different therapies. We will adjust for known predictors of survival such as stage, cytogenetic abnormalities. We will also assess the effects in the context of the latest treatments. These analyses will help us the genetic association result in the context of the changing landscape of myeloma prognostic factors and evolving treatment, Second, we will experimentally investigate the gene at the locus identified. The SNPs at the top locus are associated with expression of the nearest gene. In addition, a coding non-synonymous variant is part of the high risk haplotype. Therefore, we will experimentally manipulate in cell line models both the gene expression and the coding sequence and investigate the effect on the pathways that this gene is part of as well as overall cell proliferation rate.

描述（由申请人提供）：多发性骨髓瘤（MM）被认为是一种异质性疾病，在不同患者之间对治疗和生存的响应有很大变化。存在多种生物标志物，可以帮助预测MM预后，包括细胞遗传学标记和基因表达特征。众所周知，MM是一种部分可遗传的性状，最近的基因组广泛关联研究（GWAS）已经确定了八个与MM敏感性相关的SNP。但是，尚不清楚生殖系变异是否也可能影响MM存活。我们使用了基因组范围的缔合方法（GWAS）方法来确定是否存在可能影响592毫米患者生存的生殖系遗传变异。我们确定了在16p13上与基因座的全基因组显着关联（p = 2.8x10-10）。该发现在772例患者的单独队列中复制了。该建议将寻求扩大这些发现。我们组成了一个研究人员的联盟，研究了多发性骨髓瘤的研究，其中包括3000多名生存数据。首先，我们将研究GWA在生存和不同疗法的其他临床预测指标中发现的基因型的作用。我们将调整已知的生存预测指标，例如阶段，细胞遗传学异常。我们还将在最新治疗的背景下评估效果。这些分析将有助于我们在骨髓瘤预后因素不断变化的景观和不断发展的治疗的背景下导致我们的遗传关联，其次，我们将在所鉴定的基因座上进行实验研究。顶部基因座的SNP与最近基因的表达有关。此外，编码非同义变体是高风险单倍型的一部分。因此，我们将在细胞系模型中进行实验操纵基因表达和编码序列，并研究对该基因属性和整体细胞增殖率的途径的影响。