Genomic biomarkers for cutaneous T-cell Lymphoma

皮肤 T 细胞淋巴瘤的基因组生物标志物

• 批准号: 10321292
• 负责人: Megan S. Lim
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321292
• 关键词: Aggressive Clinical Course; Behavior; Bioinformatics; Biological Assay; Biological Markers; Biometry; Blood; Classification; Clinical; Cutaneous T-cell lymphoma; DNA Sequence Alteration; Detection; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Environment; Epigenetic Process; Exhibits; Gene Mutation; Genetic; Genomics; Goals; High-Throughput Nucleotide Sequencing; Indolent; Laboratories; Learning; Life Expectancy; Lymphoma; Measures; Methods; Modeling; Mutation; Mycosis Fungoides; Nature; Neoplasm Circulating Cells; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Performance; Peripheral; Population; Prognosis; Prognostic Marker; Prospective cohort; Recurrence; Research; Research Personnel; Retrospective cohort; Sampling; Sezary Syndrome; Skin; Skin Cancer; Staging; Subgroup; T cell receptor repertoire sequencing; T-Cell Lymphoma; T-Cell Receptor Genes; T-Lymphocyte; Testing; Time; Tumor Burden; Universities; Variant; accurate diagnosis; base; chromatin remodeling; cohort; comparative; comparative genomic hybridization; diagnostic biomarker; diagnostic criteria; diagnostic panel; diagnostic tool; disorder risk; exome sequencing; genome sequencing; genomic biomarker; improved; indexing; leukemia; mortality; neoplastic cell; next generation sequencing; novel; patient subsets; prognostic; prognostic significance; prognostic tool; prognostication; risk stratification; skin lesion; specific biomarkers; targeted treatment; tumor; whole genome

PROJECT SUMMARY Peripheral T-cell lymphomas including cutaneous T-cell lymphomas (CTCL) are poorly understood and many subtypes exhibit aggressive clinical course and high mortality with short (2-year) life expectancy after diagnosis. Poor understanding of mechanisms underlying the pathogenesis of CTCLs contributes to suboptimal diagnostic subcategorization and lack of targeted therapies. Mycosis fungoides (MF) and Sezary syndrome (SS) are two major forms of CTCL. Clinical staging and outcome of MF and SS is dependent on the quantity of neoplastic cells in the blood. While SS is an aggressive disease with poor overall survival (42.3% at 5 years and is by definition diagnosed at late stage disease, there are many patients with low tumor burden (Early-stage CTCL) who suffer from delay in diagnosis due to the subjective nature of the diagnostic criteria. The mean diagnostic delay (measured as the time from emergence of skin lesions to the diagnosis of SS) is long (4.2 year; median 2.8 years) with a significant variation (1 month to 32 years). Thus, there is a critical need for improved methods for early disease detection. Furthermore, the identification of genomic disease biomarkers that would establish early diagnosis and provide prognostic information would clearly have benefit for patients with this form of aggressive CTCL. Until recently, recurrent genetic alterations that can be exploited as diagnostic and prognostic biomarkers have not been described in these tumors. Our laboratory and other investigators recently described the genomic landscape of CTCL utilizing a comprehensive integrated strategy including whole genome sequencing, whole exome sequencing and array comparative gnomic hybridization. Highly recurrent gene mutations targeting epigenetic and chromatin remodeling and JAK-STAT and other pathways were identified in pre- treatment samples of CTCL. Based on these results, it is our central hypothesis that somatic alterations involved in the pathogenesis of CTCL in conjunction with high-throughput sequencing (HTS) of the T-cell receptor (TCR) can be utilized for early diagnosis and that genetic profiles and sensitive and quantitative detection of clonal T-cell populations can serve as prognostically-relevant biomarkers of CTCL. Accordingly, in Specific Aim 1, we propose to investigate the utility of a multivariate model based on targeted next generation sequencing (NGS) and HTS-TCR assays for the diagnosis of ES-CTCL and Late- stage CTCL (SS). In Specific Aim 2, we will investigate the impact of the genetic mutations and HTS-TCR on the prognosis of ES-CTCL and SS using a retrospective cohort. In Specific Aim 3, we will assess the performance of the multivariate model for assessing the prognosis of ES-CTCL and SS using a prospective cohort. The overall impact of this proposal is the development of targeted genomic assays that will lead to early and accurate diagnosis of CTCL and improve methods to assess early disease detection and prognosis.

项目摘要 外周T细胞淋巴瘤在内，包括皮肤T细胞淋巴瘤（CTCL）的了解不足，许多 子类型表现出激进 诊断。对CTCL发病机理的基础机制的不良理解有助于 次级诊断亚分类和缺乏靶向疗法。真菌病真菌（MF）和Sezary 综合征（SS）是CTCL的两种主要形式。 MF和SS的临床分期和结果取决于 血液中肿瘤细胞的数量。虽然SS是一种侵略性疾病，总生存率较差 （在5年时为42.3％，根据定义在晚期疾病处被诊断出，许多患者有很多 肿瘤负担（早期CTCL）因主观性质而受到诊断的延迟 诊断标准。平均诊断延迟（以皮肤病变的出现到 SS的诊断为长（4。2年；中位2。8年），其差异很大（1个月至32年）。 因此，需要改善早期疾病检测的方法的迫切需要。此外， 基因组疾病生物标志物的鉴定，这些生物标志物将早期诊断并提供预后 信息显然将对这种侵略性CTCL的患者有利。直到最近， 可以用作诊断和预后生物标志物可以利用的复发遗传改变尚未 在这些肿瘤中描述。我们的实验室和其他研究人员最近描述了基因组 CTCL的景观利用全面的综合策略，包括整个基因组测序， 整个外显子组测序和阵列比较GNOMIC杂交。高度复发的基因突变 靶向表观遗传和染色质重塑以及JAK-Stat以及其他途径在前 CTCL的治疗样本。基于这些结果，我们的核心假设是躯体改变 与T-Cell的高通量测序（HTS）结合使用CTCL的发病机理 受体（TCR）可用于早期诊断，遗传特征和敏感和 克隆T细胞种群的定量检测可以作为与预后相关的生物标志物 CTCL。因此，在特定目标1中，我们建议研究基于多元模型的实用性 针对下一代测序（NGS）和HTS-TCR分析，用于诊断ES-CTCL和晚期 CTCL阶段（SS）。在特定目标2中，我们将研究遗传突变和HTS-TCR的影响 关于ES-CTCL和SS的预后，使用回顾性队列。在特定目标3中，我们将评估 使用A评估ES-CTCL预后的多元模型的性能 潜在队列。该提案的总体影响是开发有针对性的基因组测定法 将导致对CTCL的早期，准确的诊断，并改善评估早期疾病检测的方法 和预后。