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

• 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
• 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

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.

骨髓增生异常综合征（MDS）是一组异质性和重叠的克隆性骨髓增生异常综合征（MDS）的一部分。 在造血干细胞或祖细胞中产生的疾病， (AML)骨髓增生性肿瘤（MPN）和混合型MDS/MPN实体。MDS患者有一个 进展为白血病的风险较高，预计约30%会发展为AML。MDS结局 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口的案例， MDS的对照研究，包括招募超过550例病例。在这个竞争性的续期申请中，我们 我建议利用我们的良好特征的研究人群来研究遗传学的贡献， MDS风险的变化，并评估杀伤细胞免疫球蛋白受体（KIR）对发病率的作用， 生存我们的具体目标是：1）通过与以下方面的合作，鉴定MDS的生殖系易感性变体： 2）评估KIR单倍型与MDS风险之间的关系; 和3）了解KIR基因单倍型在疾病进展和生存中的作用，总体和MDS 亚型我们假设，我们将确定预测MDS风险的变异， 在具有高风险MDS亚型的病例中更大，这些亚型更有可能进展为AML。我们进一步假设 与人群对照相比，MDS病例中KIR单倍型B的鉴定频率较低 KIR单倍型A与预后不良有关。我们将对生殖细胞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Moffitt癌症中心的200例MDS病例和1，119例年龄- 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例MDS病例和4，597例健康对照进行复制 和荟萃分析.为了提高我们检测关联的能力，我们将把分析限制在区域范围内 如通过原代细胞培养物的ATAC-seq所确定的，骨髓细胞中的开放染色质。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143 kb区域中的变异， 染色体19（位置5537984-55378670）。我们将比较两个主要的KIR基因单倍型区块（A 和B）在病例和对照中。为了评估KIR单倍型对疾病进展的影响，我们将对457例 确认MDS病例作为队列，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探索;然而， 为进一步评价提供了依据。确定MDS快速死亡的预测因素， 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，并建议 治疗的新途径连续性NK细胞疗法就是这样一种选择， 血液恶性肿瘤的治疗。

项目成果

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

• DOI: 10.1007/s10552-020-01378-x
• 发表时间: 2021-03
• 期刊: Cancer causes & control : CCC
• 作者: Yarosh R;Roesler MA;Murray T;Cioc A;Hirsch B;Nguyen P;Warlick E;Poynter JN
• 通讯作者: Poynter JN

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

• DOI: 10.1016/j.canep.2021.102090
• 发表时间: 2022-03
• 期刊: Cancer epidemiology
• 影响因子: 2.6
• 作者: Linabery AM;Roesler MA;Richardson M;Warlick ED;Nguyen PL;Cioc AM;Poynter JN
• 通讯作者: Poynter JN

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

• DOI: 10.1007/s00277-015-2422-z
• 发表时间: 2015-10
• 期刊: Annals of hematology
• 影响因子: 3.5
• 作者: Smith AR;Warlick ED;Roesler MA;Poynter JN;Richardson M;Nguyen P;Cioc A;Hirsch B;Ross JA
• 通讯作者: Ross JA

Alcohol use is not a significant contributor to myelodysplastic syndromes.

• DOI: 10.1007/s10552-020-01298-w
• 发表时间: 2020-06
• 期刊: Cancer causes & control : CCC
• 作者: Duffy EA;Nguyen PL;Cioc A;Warlick E;Roesler MA;Poynter JN
• 通讯作者: Poynter JN

Association between mitochondrial DNA haplogroup and myelodysplastic syndromes.

• DOI: 10.1002/gcc.22370
• 发表时间: 2016-09
• 期刊: Genes, chromosomes & cancer
• 作者: Poynter JN;Richardson M;Langer E;Hooten AJ;Roesler M;Hirsch B;Nguyen PL;Cioc A;Warlick E;Ross JA
• 通讯作者: Ross JA