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
基本信息
- 批准号:10506155
- 负责人:
- 金额:$ 26.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Acute Myelocytic LeukemiaAffectAlgorithmsAneuploidyAspirate substanceBiological AssayBone MarrowBone Marrow CellsBone Marrow DiseasesBone marrow failureCLIA certifiedCharacteristicsChromosome DeletionChromosome abnormalityClinicalClinical TrialsClinical assessmentsCytogenetic AnalysisCytogeneticsDNA Sequence AlterationDetectionDiagnosisDiagnosticDisadvantagedDiseaseDysmyelopoietic SyndromesEnrollmentEvaluationEventFailureFrequenciesFutureGeneticGenetic RiskGenomicsGoalsInformaticsInterventionKaryotype determination procedureLaboratoriesLoss of HeterozygosityMalignant NeoplasmsMarrowMetaphaseMethodsMorbidity - disease rateMutationMyeloproliferative diseaseNatural HistoryOutcomePatientsPerformancePersonsPrecision therapeuticsProspective cohortResolutionRiskRisk AssessmentSamplingSecondary acute myeloid leukemiaSecondary toStem cell transplantTestingVariantaggressive therapyclinically relevantcohortdetection limitgene panelgenetic profilinggenetic risk assessmentgenome sequencinghuman old age (65+)improvedin silicomortalitypatient stratificationpredict clinical outcomeprediction algorithmprognosticprospectiveresearch clinical testingrisk predictionrisk stratificationsuccesstumorwhole genome
项目摘要
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遗传分析和风险分层的患者,
骨髓增生异常综合征(MDS)使用临床全基因组测序。MDS是一种异质性
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而常常是致命的
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
为了延长生存期,并尽量减少与更多相关的发病率和死亡率的可能性,
积极的治疗骨髓增生异常综合征患者骨髓细胞中期染色体核型分析
是MDS风险评估算法的重要组成部分,用于检测染色体缺失,
重复和非整倍体与不同的临床结果相关。尽管染色体核型分析
虽然它已经被有效地使用了几十年,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特征不完整。我们最近开发了
经验证的ChromoSeq,一种稳健的CAP/CLIA兼容的全基因组测序(WGS)检测方法,用于遗传
骨髓恶性肿瘤患者的特征分析。我们表明,该方法对临床诊断的敏感性为100%。
AML中的相关细胞遗传学异常,并在高达25%的患者中确定了其他细胞遗传学事件
标准细胞遗传学检测不到的基因这些发现包括新的风险定义染色体
在近15%的患者中发现异常,从而更好地预测临床结果。虽然MDS
AML和AML是密切相关的疾病,它们共享许多特征,基因组特征和细胞免疫学特征。
MDS的组成不同。此外,使用ChromoSeq结果形成现有MDS风险组,
未经临床验证。我们假设优化ChromoSeq全基因组
MDS样本的测序分析将提高遗传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样本的组合
验证ChromoSeq用于MDS患者的遗传分析和风险评估。我们将首先使用回溯
MDS样品,以优化和验证我们现有的CAP/CLIA兼容的ChromoSeq WGS检测,
检测低频率突变、拷贝数改变(CNA)和拷贝中性杂合性丢失
(CNLOH),其在MDS中常见(Aim 1; UH 2组分)。然后,我们将使用一个前瞻性MDS队列,
建立ChromoSeq检测用于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CAP/CLIA兼容的ChromoSeq检测试剂盒在MDS样本中的使用,
用于未来的干预性临床试验和该恶性肿瘤患者的常规临床试验。
项目成果
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Genome sequencing for evaluating the efficacy, specificity, and safety of human genome editing
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- 批准号:
10667893 - 财政年份:2023
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$ 26.15万 - 项目类别:
A Rapid and Comprehensive Approach for Clinical Genomic Profiling in Lung Cancer
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10613055 - 财政年份:2023
- 资助金额:
$ 26.15万 - 项目类别:
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