Genetic Biomarkers for Risk Assessment of Peripheral T-Cell Lymphomas

描述（由申请人提供）：外周t细胞淋巴瘤（PTCLs）是一组尚不清楚的侵袭性血液恶性肿瘤。只有三分之一的患者能在确诊后存活5年。大多数患者接受化疗方案（CHOP），最初是为其他类型的淋巴瘤设计的，在PTCL中是次优的。通过干细胞移植治疗CHOP已显示出希望，但毒性增加。较新的化疗药物对一些患者也显示出益处。然而，目前很少有生物标志物测试可用于确定哪种治疗方法最适合特定患者。基因检测在其他血液学恶性肿瘤患者的个体化治疗中起着关键作用，但由于PTCL的遗传学尚未完全了解，这种方法在PTCL中的应用一直受到阻碍。基于对生物标志物预测PTCL临床行为的迫切需求，我们制定了三个需要回答的基本问题：1)PTCL复发性遗传异常是什么？2)哪些遗传生物标志物最能增强当前的风险评估工具？3)哪些遗传生物标志物可预测PTCL治疗药物的化学敏感性？我们的研究团队在了解PTCL的遗传学方面做出了重大贡献，因此有能力以高度创新和全面的方式解决这些问题。在Aim 1中，我们将使用生物信息学方法分析66个PTCL肿瘤样本的发现集，我们已经对这些样本进行了下一代测序和基因表达谱分析。在Aim 2中，我们将把我们之前的发现与他人的发现以及Aim 1中最优先的候选物结合起来，以确定在332个ptcl的独立验证集中，哪种生物标志物组合对识别高风险和低风险患者最有帮助。在Aim 3中，我们将确定特定的遗传异常如何影响PTCL细胞对化疗药物的敏感性。我们相信这些研究极有可能改变PTCL患者的临床管理。在短期内，我们预计改善风险评估将导致患者接受标准治疗、强化治疗和实验治疗的选择发生变化。从长远来看，我们相信我们的结果将允许根据PTCL肿瘤组织中遗传异常的模式来个性化选择化疗药物。

DESCRIPTION (provided by applicant): Peripheral T-cell lymphomas (PTCLs) represent a poorly understood group of aggressive hematologic malignancies. Only one-third of patients survive 5 years from the time of diagnosis. Most patients receive a chemotherapy regimen (CHOP) that originally was designed for other types of lymphoma and is suboptimal in PTCL. Following CHOP by stem-cell transplantation has shown promise, but carries increased toxicity. Newer chemotherapy drugs also have shown benefits in some patients. However, few biomarker tests currently are available to identify which therapy is most appropriate for a given patient. Genetic testing plays a key role in stratifying patients for individualized therapy in othr hematologic malignancies, but application of this approach to PTCL has been hindered because the genetics of PTCL are incompletely understood. Based on the urgent need for biomarkers to predict clinical behavior in PTCL, we formulated three fundamental questions that need to be answered: 1) What are the recurrent genetic abnormalities in PTCL? 2) Which genetic biomarkers best enhance current risk assessment tools? 3) Which genetic biomarkers predict chemosensitivity to drugs used to treat PTCL? Our research team has made major contributions to understanding the genetics of PTCL and thus is well equipped to address these questions in a highly innovative and comprehensive way. In Aim 1, we will use a bioinformatic approach to analyze a discovery set of 66 PTCL tumor samples on which we already have performed next generation sequencing and gene expression profiling. In Aim 2, we will combine our previous discoveries with findings by others and the highest priority candidates from Aim 1 to identify which combination of biomarkers is most helpful in identifying high- and low-risk patients in an independent validation set of 332 PTCLs. In Aim 3, we will determine how particular genetic abnormalities contribute to the sensitivity of PTCL cells to chemotherapeutic drugs. We believe these studies are highly likely to change the clinical management of PTCL patients. In the short term, we anticipate that improving risk assessment will lead to changes in selection of patients to receive standard vs. intensified vs. experimental therapy. In the longer term, we believe our results will allow individualized selection of chemotherapy drugs based on the pattern of genetic abnormalities in PTCL tumor tissue.