Genomic biomarkers for cutaneous T-cell Lymphoma

项目摘要 外周T细胞淋巴瘤，包括皮肤T细胞淋巴瘤（CTCL）了解甚少，许多 亚型表现出侵略性的临床过程和高死亡率，预期寿命短（2年）， 诊断.对CTCL发病机制的认识不足有助于 次优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两种主要形式。MF和SS的临床分期和结局取决于 血液中肿瘤细胞的数量虽然SS是一种侵袭性疾病， (42.3%，并且根据定义在晚期疾病时被诊断，有许多患者具有低 肿瘤负荷（早期CTCL），由于主观性质而导致诊断延迟。 诊断标准平均诊断延迟（测量为从出现皮肤病变到出现皮肤病变的时间） 诊断为SS）的时间较长（4.2年;中位数2.8年），具有显著变化（1个月至32年）。 因此，迫切需要用于早期疾病检测的改进方法。而且 鉴定基因组疾病生物标志物，其将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复发性遗传改变尚未被 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 利用包括全基因组测序在内的全面综合战略的CTCL前景， 全外显子组测序和阵列比较基因组杂交。高度重复发生的基因突变 靶向表观遗传和染色质重塑以及JAK-STAT和其他途径， CTCL的治疗样品。基于这些结果，我们的中心假设是， 参与CTCL发病机制的T细胞高通量测序（HTS） 受体（TCR）可用于早期诊断，基因谱和敏感性， 克隆T细胞群的定量检测可以作为免疫学相关的生物标志物， CTCL。因此，在具体目标1中，我们建议研究基于以下的多变量模型的效用： 靶向下一代测序（NGS）和HTS-TCR测定用于诊断ES-CTCL和晚期- CTCL（SS）期。在具体目标2中，我们将研究基因突变和HTS-TCR的影响。 ES-CTCL和SS的预后。在具体目标3中，我们将评估 多变量模型用于评估ES-CTCL和SS预后的性能， 前瞻性队列这一提议的总体影响是靶向基因组测定的发展， 将导致CTCL的早期和准确诊断，并改善评估早期疾病检测的方法 和预后。

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.