Genetic evolution in recurrent T-cell lymphoma

复发性 T 细胞淋巴瘤的遗传进化

• 批准号: 404788958
• 负责人: Dr. Alexandra Butzmann
• 金额: --
• 依托单位: School of Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404788958?language=en
• 关键词: Genetic; evolution; recurrent; cell; lymphoma

Peripheral T-cell lymphomas (PTCL) are fatal in 60% of the patients, and the prognosis hasn’t changed in the past two decades. This is attributable to a lack of information for classification, risk factors and pathogenesis. Due to the rare prevalence of PTCL, throughout studies, and studies with a higher statistical power are missing. Recent studies show recurrent mutations in the two major sub-type angioimmunoblastic (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL, NOS), but the clinical impact is unknown. I claim, that a detailed molecular investigation can help understanding these neoplasms and therefor will help to achieve better outcomes for PTCL patients. I want to study the genetic landscape and evolution of the two major sub-groups of PTCL, AITL and PTCL, NOS, by combining important methods of Next Generation Sequencing: Whole Exome Sequencing, exome targeted deep sequencing and whole transcriptome RNA-sequencing. My proposed study consists of two main parts. In the first part I will sequence 37 PTCL samples at diagnosis and recurrence and I will identify common and different mutations at both stages, as well as sub-group specific mutations. Using the results of that first part I will, together with specialist in the field of hematology and hematopathology, design an exome targeted panel and discuss the whole transcriptome RNA-sequencing design. Consequentially, I will conduct exome targeted sequencing and whole transcriptome RNA-sequencing on 123 PTCL samples at diagnosis (n=123) and recurrence (n=86). With modern sequencing technologies, I will be able to identify low allele frequency variants within the tumor samples, that were identified as sensitive markers for prognostication in other cancers. Finally, I will analyze all resulting data, gene expression profiles and genetic landscape, in the context of clinical data, morphologic features and perform a pathway analysis. With analyzing 150 patient samples overall, my proposed study will be the first, that provides an exhaustive overview of the genetic changes happening during progression of PTCL within the clinical context.

外周T细胞淋巴瘤(PTCL)在60%的患者中是致命的，在过去的二十年里预后没有改变。这是由于缺乏关于分类、危险因素和发病机制的信息。由于PTCL的罕见患病率，纵观所有研究，以及具有较高统计能力的研究都缺失。最近的研究表明，复发突变存在于血管免疫母细胞瘤(AITL)和外周T细胞淋巴瘤(PTCL，NOS)两大亚型中，但其临床影响尚不清楚。我认为，详细的分子研究有助于了解这些肿瘤，从而有助于PTCL患者获得更好的预后。我想通过结合下一代测序的重要方法：全外显子组测序、外显子组靶向深度测序和全转录组RNA测序，研究PTCL的两个主要亚群AITL和PTCL的遗传格局和进化。我提出的研究包括两个主要部分。在第一部分中，我将在诊断和复发时对37例PTCL样本进行测序，并在两个阶段识别共同和不同的突变，以及亚组特有的突变。利用第一部分的结果，我将与血液学和血液病理学领域的专家一起，设计一个外显子组靶向小组，并讨论整个转录组RNA测序设计。因此，我将对123例初诊(n=123)和复发(n=86)的PTCL标本进行外显子组靶向测序和全转录组RNA测序。有了现代测序技术，我将能够在肿瘤样本中识别出低等位基因频率的变异，这些变异被认为是其他癌症预后的敏感标记。最后，我将在临床数据、形态特征的背景下分析所有结果数据、基因表达谱和遗传格局，并执行路径分析。由于总共分析了150个患者样本，我提议的研究将是第一个，它提供了在临床背景下PTCL进展过程中发生的基因变化的详尽概述。