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: 9884667
• 负责人: Megan S. Lim
• 金额: $ 63.34万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9884667
• 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; Prognostic Marker; Prospective cohort; Recurrence; Research; Research Personnel; Retrospective cohort; Risk stratification; Sampling; Sezary Syndrome; Skin; Skin Cancer; Staging; Subgroup; T-Cell Lymphoma; T-Cell Receptor; 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 panel; disorder risk; exome sequencing; genetic profiling; genome sequencing; genomic biomarker; improved; indexing; leukemia; mortality; neoplastic cell; next generation sequencing; novel; outcome forecast; patient subsets; prognostic; prognostic significance; prognostic tool; 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.

项目概要 人们对外周 T 细胞淋巴瘤（包括皮肤 T 细胞淋巴瘤 (CTCL)）知之甚少，并且许多 亚型表现出侵袭性临床病程和高死亡率，且预期寿命短（2年） 诊断。对 CTCL 发病机制的了解不足导致 次优的诊断亚分类和缺乏靶向治疗。蕈样肉芽肿 (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 是一种侵袭性疾病，总体生存率较差 （5 年时为 42.3%，根据定义，诊断时已处于疾病晚期，有许多患者患有低血压 肿瘤负荷（早期 CTCL）由于主观性而导致诊断延迟的患者 诊断标准。平均诊断延迟（以从出现皮肤病变到出现症状的时间来衡量） SS 诊断时间较长（4.2 年；中位 2.8 年），且差异显着（1 个月至 32 年）。 因此，迫切需要改进早期疾病检测的方法。此外， 鉴定基因组疾病生物标志物，以建立早期诊断并提供预后 这些信息显然对患有这种形式的侵袭性 CTCL 的患者有益。直到最近， 可用作诊断和预后生物标志物的反复发生的基因改变尚未得到证实。 描述了这些肿瘤。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，包括全基因组测序， 全外显子组测序和芯片比较基因组杂交。高频率基因突变 靶向表观遗传和染色质重塑以及 JAK-STAT 和其他途径在预 CTCL的治疗样本。基于这些结果，我们的中心假设是体细胞改变 结合 T 细胞高通量测序 (HTS) 参与 CTCL 的发病机制 受体（TCR）可用于早期诊断，并且遗传图谱和敏感且 克隆 T 细胞群的定量检测可以作为预后相关的生物标志物 CTCL。因此，在具体目标 1 中，我们建议研究基于 靶向下一代测序 (NGS) 和 HTS-TCR 检测用于诊断 ES-CTCL 和晚期 CTCL 阶段（SS）。在具体目标 2 中，我们将研究基因突变和 HTS-TCR 的影响 使用回顾性队列研究 ES-CTCL 和 SS 的预后。在具体目标 3 中，我们将评估 使用多变量模型评估 ES-CTCL 和 SS 预后的性能 前瞻性队列。该提案的总体影响是开发靶向基因组检测， 将导致 CTCL 的早期准确诊断，并改进评估早期疾病检测的方法 和预后。