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.

该建议的目的是改善遗传谱和风险分层的患者