Genomic biomarkers for cutaneous T-cell Lymphoma

项目总结 外周T细胞淋巴瘤，包括皮肤T细胞淋巴瘤(CTCL)，人们对其了解很少，许多 亚型表现出侵袭性的临床病程和高死亡率，术后预期寿命较短(2年) 诊断。对CTCL发病机制的认识不足是导致CTCL发病的原因之一 次优的诊断亚类和缺乏针对性的治疗。真菌病(MF)与Sezary 综合征(SS)是CTCL的两种主要形式。MF和SS的临床分期和预后取决于 血液中肿瘤细胞的数量。而SS是一种侵袭性疾病，总体存活率很低 (42.3%在5年，根据定义被诊断为晚期疾病，有许多患者低 肿瘤负担(早期CTCL)由于肿瘤的主观性质而延误诊断 诊断标准。平均诊断延迟(衡量的是从皮损出现到 SS的诊断)时间长(4.2年；中位数2.8年)，差异显著(1个月至32年)。 因此，迫切需要改进疾病早期检测的方法。此外， 基因组疾病生物标志物的鉴定将建立早期诊断和提供预后 信息显然对患有这种侵袭性CTCL的患者有好处。直到最近， 可作为诊断和预后生物标记物的复发性遗传改变尚未被发现 在这些肿瘤中描述的。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， 全外显子组测序和阵列比较基因组杂交。高复发率基因突变 靶向表观遗传和染色质重塑以及JAK-STAT等通路在Pre-Pre中被确定 CTCL的处理样品。基于这些结果，我们的中心假设是躯体变化 与T细胞高通量测序(HTS)共同参与CTCL的发病 受体(TCR)可用于早期诊断，基因图谱和敏感性和 克隆性T细胞群体的定量检测可作为与预后相关的生物标志物 CTCL。因此，在具体目标1中，我们建议研究基于以下条件的多变量模型的实用性 靶向下一代测序(NGS)和HTS-TCR检测在ES-CTCL和晚期CTCL诊断中的应用 CTCL分期(SS)。在特定目标2中，我们将研究基因突变和HTS-TCR的影响 应用回顾性队列研究ES-CTCL和SS的预后。在具体目标3中，我们将评估 多变量模型对ES-CTCL和SS预后的评估 未来的队列。这项提议的总体影响是开发具有针对性的基因组分析， 将有助于CTCL的早期和准确诊断，并改进评估早期疾病发现的方法 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.