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.

该提案的目标是改善患有以下疾病的患者的基因分析和风险分层 使用临床全基因组测序治疗骨髓增生异常综合征（MDS）。 MDS 是一种异质 一组克隆性骨髓疾病，由于骨髓衰竭或进展为急性髓系疾病，通常是致命的 白血病（AML）。因此，准确预测进展风险对于 MDS 患者的管理至关重要 为了延长生存并尽量减少与更多相关的发病率和死亡率的可能性 积极的治疗。通过中期核型分析对MDS患者骨髓细胞进行细胞遗传学分析 是 MDS 风险评估算法的重要组成部分，用于检测染色体缺失， 与不同临床结果相关的重复和非整倍体。尽管核型分析已 虽然它已经有效使用了几十年，但它有几个缺点。这些包括低基因组分辨率和高 失败率可能导致某些患者的遗传风险概况不完整。我们最近开发并 经过验证的 ChromoSeq，一种强大的符合 CAP/CLIA 标准的全基因组测序 (WGS) 检测方法，用于遗传检测 骨髓恶性肿瘤患者的概况分析。我们证明该方法在临床上的敏感性为 100% AML 中的相关细胞遗传学异常，并在高达 25% 的患者中发现了其他细胞遗传学事件 标准细胞遗传学未检测到。这些发现包括新的风险定义染色体 近 15% 的患者出现异常，从而更好地预测临床结果。虽然MDS 和 AML 是密切相关的疾病，它们具有许多共同的特征、基因组特征和细胞特征 MDS 的组成是不同的。此外，使用 ChromoSeq 结果形成现有的 MDS 风险组已 尚未经过临床验证。我们假设 ChromoSeq 全基因组的优化 MDS 样本测序分析将提高基因分析和风险分层的准确性 MDS 患者。在这里，我们建议结合使用回顾性和前瞻性临床 MDS 样本 验证 ChromoSeq 在 MDS 患者中的基因分析和风险评估。我们首先使用回顾法 MDS 样本用于优化和验证我们现有的符合 CAP/CLIA 标准的 ChromoSeq WGS 检测，以改进 检测低频突变、拷贝数改变 (CNA) 和杂合性的拷贝中性丢失 (CNLOH)，这在 MDS 中很常见（目标 1；UH2 成分）。然后我们将使用前瞻性 MDS 队列来 确定 ChromoSeq 检测对 MDS 患者基因组分析和风险评估的临床有效性。 该项目将扩大符合 CAP/CLIA 标准的 ChromoSeq 检测在 MDS 样本中的使用，以便 可用于未来对该恶性肿瘤患者的介入临床试验和常规临床测试。