Whole Genome Sequencing for Genomic Evaluation and Risk Stratification of Patients with Myelodysplastic Syndromes

全基因组测序用于骨髓增生异常综合征患者的基因组评估和风险分层

• 批准号: 10506155
• 负责人: ERIC J DUNCAVAGE
• 金额: $ 26.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506155
• 关键词: Acute Myelocytic Leukemia; Affect; Algorithms; Aneuploidy; Aspirate substance; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Bone marrow failure; CLIA certified; Characteristics; Chromosome Deletion; Chromosome abnormality; Clinical; Clinical Trials; Clinical assessments; Cytogenetic Analysis; Cytogenetics; DNA Sequence Alteration; Detection; Diagnosis; Diagnostic; Disadvantaged; Disease; Dysmyelopoietic Syndromes; Enrollment; Evaluation; Event; Failure; Frequencies; Future; Genetic; Genetic Risk; Genomics; Goals; Informatics; Intervention; Karyotype determination procedure; Laboratories; Loss of Heterozygosity; Malignant Neoplasms; Marrow; Metaphase; Methods; Morbidity - disease rate; Mutation; Myeloproliferative disease; Natural History; Outcome; Patients; Performance; Persons; Precision therapeutics; Prospective cohort; Resolution; Risk; Risk Assessment; Sampling; Secondary acute myeloid leukemia; Secondary to; Stem cell transplant; Testing; Variant; aggressive therapy; clinically relevant; cohort; detection limit; gene panel; genetic profiling; genetic risk assessment; genome sequencing; human old age (65+); improved; in silico; mortality; patient stratification; predict clinical outcome; prediction algorithm; prognostic; prospective; research clinical testing; risk prediction; risk stratification; success; tumor; whole genome

The goal of this proposal is to improve genetic profiling and risk stratification for patients with myelodysplastic syndromes (MDS) using clinical whole-genome sequencing. MDS is a heterogenous group of clonal bone marrow disorders that are often fatal due to marrow failure or progression to acute myeloid leukemia (AML). Accurate prediction progression risk is therefore critical for the management of MDS patients in order to prolong survival and minimize the potential for morbidity and mortality associated with more aggressive treatments. Cytogenetic analysis of bone marrow cells from MDS patients via metaphase karyotyping is an essential component of MDS risk assessment algorithms, and is used to detect chromosomal deletions, duplications, and aneuploidies that are associated with differential clinical outcomes. Although karyotyping has been used effectively for decades, it has several disadvantages. These include low genomic resolution and high failure rates that can result in incomplete genetic risk profiles for some patients. We recently developed and validated ChromoSeq, a robust CAP/CLIA-compliant whole-genome sequencing (WGS) assay for genetic profiling of patients with myeloid malignancies. We showed that this method was 100% sensitivity for clinically relevant cytogenetic abnormalities in AML and identified additional cytogenetic events in up to 25% of patients that were not detected by standard cytogenetics. These findings included new risk-defining chromosomal abnormalities in almost 15% of patients, which resulted in better prediction of clinical outcomes. Although MDS and AML are closely related diseases that share many features, the genomic characteristics and cellular composition of MDS is distinct. In addition, the use of ChromoSeq results to form existing MDS risk groups has not been clinically validated. We hypothesize that optimization of the ChromoSeq whole-genome sequencing assay for MDS samples will improve the accuracy of genetic profiling and risk stratification of MDS patients. Here we propose to use a combination of retrospective and prospective clinical MDS samples to validate ChromoSeq for genetic profiling and risk assessment in MDS patients. We will first use retrospective MDS samples to optimize and validate our existing CAP/CLIA-compliant ChromoSeq WGS assay to improve the detection of low frequency mutations, copy number alterations (CNAs) and copy neutral loss of heterozygosity (CNLOH), which are common in MDS (Aim 1; UH2 component). We will then use a prospective MDS cohort to establish the clinical validity of ChromoSeq assay for genomic profiling and risk assessment of MDS patients. This project will expand the use of the CAP/CLIA-compliant ChromoSeq assay to MDS samples so that it may be used for future interventional clinical trials and routine clinical testing of patients with this malignancy.

该提案的目的是改善患有患者的基因分析和风险分层 使用临床全基因组测序，骨髓增生综合征（MDS）。 MDS是异源 一组克隆骨髓疾病通常由于骨髓衰竭或急性髓样而致命 白血病（AML）。因此，准确的预测进展风险对于MDS患者的管理至关重要 为了延长生存并最大程度地减少与更多相关的发病率和死亡率的潜力 积极的治疗。通过中期核分型对MDS患者的骨髓细胞的细胞遗传学分析 是MDS风险评估算法的重要组成部分，用于检测染色体缺失， 重复和与差异临床结果相关的非整倍性。虽然核分型具有 数十年来有效使用，有几个缺点。这些包括低基因组分辨率和高 失败率可能导致某些患者不完整的遗传风险概况。我们最近开发了 经过验证的Chromoseq，一种可靠的CAP/CLIA兼容的全基因组测序（WGS）测定 骨髓恶性肿瘤患者的分析。我们表明，这种方法对临床上的敏感性100％ AML的相关细胞遗传学异常，并确定了多达25％的患者的其他细胞遗传学事件 标准细胞遗传学未检测到的。这些发现包括新的风险定义染色体 几乎15％的患者中的异常，导致对临床结局的预测更好。虽然MD AML是具有许多特征，基因组特征和细胞的密切相关疾病 MD的组成是不同的。此外，使用Chromoseq结果形成现有的MDS风险组具有 未经临床验证。我们假设Chromoseq全基因组的优化 MDS样品的测序测定将提高基因分析和风险分层的准确性 MDS患者。在这里，我们建议使用回顾性和前瞻性临床MDS样品的组合 验证MDS患者的Chromoseq进行基因分析和风险评估。我们将首先使用回顾 MDS样品以优化和验证我们现有的CAP/CLIA符合Chromoseq WGS测定法以改进 检测低频突变，拷贝数变化（CNA）和副本中性杂合性丧失 （CNLOH），在MDS中很常见（AIM 1; UH2组件）。然后，我们将使用潜在的MDS队列 建立Chromoseq分析对MDS患者的基因组分析和风险评估的临床有效性。 该项目将将符合CAP/CLIA的Chromoseq分析的使用扩展到MDS样品，以便它可以 可用于这种恶性肿瘤患者的将来的介入临床试验和常规临床测试。