Predictors of Myelodysplastic Syndrome in Minnesota

明尼苏达州骨髓增生异常综合征的预测因素

基本信息

批准号：
10352447
负责人：
Jenny N. Poynter
金额：
$ 46.31万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352447
关键词：
AML/MDS ATAC-seq Acute Myelocytic Leukemia Adult Affect Age Alleles Allogenic Area Biological Biology Cancer Center Case-Control Studies Cell Culture Techniques Cells Cessation of life Childhood Chromatin Chromosome 19 Clinical Clinical Research Clinical Trials Collaborations DNA Data Disease Disease Progression Dysmyelopoietic Syndromes Early Diagnosis Etiology Evaluation Family Frequencies Funding Genetic Genetic Variation Genome Genotype Haplotypes Hematologic Neoplasms Hematological Disease Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Hybrids Immunologic Surveillance Incidence Individual Innate Immune System Investigation Killer Cells Knowledge Leukemic Cell Ligands Malignant Neoplasms Measures Meta-Analysis Minnesota Myelodysplastic/Myeloproliferative Disease Myeloid Cells Myeloproliferative disease NK cell therapy Natural Killer Cells Outcome Pathway interactions Patients Penetrance Persons Pharmacology Play Population Control Population Study Positioning Attribute Predisposition Prevention Primary Cell Cultures Prognosis Questionnaires Receptor Gene Reporting Research Personnel Risk Risk Estimate Role Sample Size Sampling Single Nucleotide Polymorphism Subgroup Susceptibility Gene Syndrome System Testing Transplantation United States Variant base case control cohort disorder risk epidemiology study follow-up genome wide association study high risk immunoglobulin receptor improved leukemia member novel patient subsets population based public health relevance recruit stem cells study population telomere therapy development

项目摘要

Abstract Myelodysplastic syndromes (MDS) are part of a heterogeneous and overlapping group of clonal diseases that arise in the hematopoietic stem or progenitor cells and also include acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and the hybrid MDS/MPN entities. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop AML. Outcomes for MDS are poor, with 5 year relative survival estimates below 50%, suggesting that early detection and prevention could have a large impact. During our initial funding period, we conducted the first population-based case control study of MDS, including recruitment of over 550 cases. In this competing renewal application, we propose to capitalize on our well-characterized study population to investigate the contribution of genetic variation to MDS risk and to evaluate the role of the killer cell immunoglobulin receptors (KIR) on incidence and survival. Our specific aims are to: 1) Identify germline susceptibility variants for MDS through collaboration with the MDS Clinical Research Consortium; 2) Evaluate the relationship between KIR haplotypes and risk of MDS; and 3) Understand the role of KIR gene haplotypes in disease progression and survival, overall and by MDS subtype. We hypothesize that we will identify variants that predict MDS risk and that risk estimates will be larger in cases with high risk MDS subtypes who are more likely to progress to AML. We further hypothesize that KIR haplotype B will be identified at a lower frequency in MDS cases compared with population controls and that KIR haplotype A will be associated with worse prognosis. We will genotype germline DNA samples from 465 MDS cases from our case-control study, 200 MDS cases from Moffitt Cancer Center and 1,119 age- matched population controls using the Illumina HumanOmni2.5 array. We will use available genotyping data from 1,700 MDS cases from the MDS Clinical Research Consortium and 4,597 healthy controls for replication and meta-analysis. In order to improve our power to detect associations, we will restrict our analysis to regions of open chromatin in myeloid cells as determined by ATAC-seq of primary cell cultures. For Aim 2, targeted capture and sequencing will be used to measure variation in the 143kb region containing the KIR genes on chromosome 19 (position 5537984-55378670). We will compare the two main KIR gene haplotype blocks (A and B) in cases and controls. To evaluate the impact of KIR haplotypes on progression, we will treat the 457 confirmed MDS cases as a cohort and evaluate associations between KIR haplotype and progression to AML and survival. The role of common genetic variation is largely unexplored in MDS; however, the few studies that have been conducted provide a rationale for further evaluation. Identifying predictors of rapid death from MDS, such as KIR haplotypes or alleles, could provide clues to the underlying biology in this subgroup and suggest new avenues for therapy. Adoptive NK cell therapy is one such option that is already in development for treatment of hematologic malignancy.

摘要骨髓增生异常综合征 (MDS) 是一组异质且重叠的克隆性疾病的一部分。造血干细胞或祖细胞中出现的疾病，还包括急性髓系白血病 (AML)、骨髓增生性肿瘤 (MPN) 和混合 MDS/MPN 实体。患有 MDS 的个体有进展为白血病的风险很高，大约 30% 预计会发展为 AML。 MDS 的结果较差，5 年相对生存率估计低于 50%，这表明早期发现和预防可能会产生很大的影响。在我们最初的资助期间，我们进行了第一个基于人群的案例 MDS 对照研究，包括招募超过 550 例病例。在这个竞争性续订申请中，我们提议利用我们特征明确的研究人群来调查遗传的贡献 MDS 风险的变化并评估杀伤细胞免疫球蛋白受体 (KIR) 对发病率和生存。我们的具体目标是： 1) 通过与以下机构合作识别 MDS 种系易感性变异： MDS 临床研究联盟； 2）评估KIR单倍型与MDS风险的关系； 3) 了解 KIR 基因单倍型在疾病进展和生存中的总体作用和 MDS 的作用亚型。我们假设我们将识别预测 MDS 风险的变体，并且风险估计将是具有高风险 MDS 亚型且更有可能进展为 AML 的病例更大。我们进一步假设与人群对照相比，MDS 病例中 KIR 单倍型 B 的识别频率较低并且 KIR 单倍型 A 与较差的预后相关。我们将对种系 DNA 样本进行基因分型来自我们病例对照研究的 465 例 MDS 病例、来自莫菲特癌症中心的 200 例 MDS 病例和 1,119 名年龄- 使用 Illumina HumanOmni2.5 阵列匹配群体对照。我们将使用可用的基因分型数据来自 MDS 临床研究联盟的 1,700 个 MDS 病例和 4,597 个健康对照进行复制和荟萃分析。为了提高我们检测关联的能力，我们将把我们的分析限制在区域内通过原代细胞培养物的 ATAC-seq 测定骨髓细胞中开放染色质的变化。对于目标 2，有针对性捕获和测序将用于测量包含 KIR 基因的 143kb 区域的变异 19 号染色体（位置 5537984-55378670）。我们将比较两个主要的 KIR 基因单倍型块（A B) 病例和对照。第457章将确诊的 MDS 病例作为一个队列，并评估 KIR 单倍型与 AML 进展之间的关联和生存。常见遗传变异在 MDS 中的作用在很大程度上尚未被探索。然而，少数研究表明已开展的工作为进一步评估提供了理由。确定 MDS 快速死亡的预测因子，例如 KIR 单倍型或等位基因，可以为该亚组的潜在生物学提供线索，并表明新的治疗途径。过继性 NK 细胞疗法就是这样一种选择，已经在开发中血液系统恶性肿瘤的治疗。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota.

明尼苏达州骨髓增生异常综合征 (MDS) 的一项基于人群的研究中与患者造血细胞移植 (HCT) 相关的因素。

DOI：
发表时间：
2015-10
期刊：
影响因子：
3.5
作者：
Smith, Angela R;Warlick, Erica D;Roesler, Michelle A;Poynter, Jenny N;Richardson, Michaela;Nguyen, Phuong;Cioc, Adina;Hirsch, Betsy;Ross, Julie A
通讯作者：
Ross, Julie A

Risk factors for de novo and therapy-related myelodysplastic syndromes (MDS).

新发和治疗相关骨髓增生异常综合征 (MDS) 的危险因素。

DOI：
发表时间：
2021-03
期刊：
影响因子：
0
作者：
Yarosh, Rina;Roesler, Michelle A;Murray, Thomas;Cioc, Adina;Hirsch, Betsy;Nguyen, Phuong;Warlick, Erica;Poynter, Jenny N
通讯作者：
Poynter, Jenny N

Personal history of autoimmune disease and other medical conditions and risk of myelodysplastic syndromes.

自身免疫性疾病和其他医疗状况的个人病史以及骨髓增生异常综合征的风险。

DOI：
发表时间：
2022-02
期刊：
影响因子：
2.6
作者：
Linabery, Amy M;Roesler, Michelle A;Richardson, Michaela;Warlick, Erica D;Nguyen, Phuong L;Cioc, Adina M;Poynter, Jenny N
通讯作者：
Poynter, Jenny N

Association between mitochondrial DNA haplogroup and myelodysplastic syndromes.

线粒体 DNA 单倍群与骨髓增生异常综合征之间的关联。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Poynter, Jenny N;Richardson, Michaela;Langer, Erica;Hooten, Anthony J;Roesler, Michelle;Hirsch, Betsy;Nguyen, Phuong L;Cioc, Adina;Warlick, Erica;Ross, Julie A
通讯作者：
Ross, Julie A

Alcohol use is not a significant contributor to myelodysplastic syndromes.

饮酒并不是骨髓增生异常综合征的重要诱因。

DOI：
发表时间：
2020-06
期刊：
影响因子：
0
作者：
Duffy, Elizabeth A;Nguyen, Phuong L;Cioc, Adina;Warlick, Erica;Roesler, Michelle A;Poynter, Jenny N
通讯作者：
Poynter, Jenny N