Molecular diagnostic and prognostic signatures for PTCL

摘要 在西方，外周T细胞淋巴瘤(PTCL)约占所有NHL的10%-12% 采用标准化疗后，患者预后一般较差。另一个重大挑战是， 使用目前的诊断方法，大约30%-50%的PTCL病例不能被归类为 具体实体，并归类为PTCL-未另行说明(PTCL-NOS)。更常见的 PTCL实体被WHO分类识别，我们定义了强大的分子基因表达 可区分五种PTCL实体的特征：血管免疫母细胞性T细胞淋巴瘤(AITL)， 间变性大细胞淋巴瘤(ALK(+)ALCL)，ALK阴性 间变性大细胞淋巴瘤(ALK(-)ALCL)、成人T细胞白血病/淋巴瘤(ATLL)和结外 自然杀伤/T细胞淋巴瘤(ENKTCL)。PTCL-NOS现在可以分成两个不同的分子 亚组(Tbx21和GATA3亚组)。AITL的预后模型也已开发出来。 总体而言，这些占所有PTCL的80%以上。这项提议的目的是巩固这些 可应用于福尔马林的单一技术平台中的诊断和预后签名 固定石蜡包埋组织(FFPET)，以提高PTCL诊断的标准化和准确性。 这一平台不仅适用于常规的临床应用，还将有助于对患者进行分层 新治疗剂的前瞻性临床试验。我们将在CLIA设置中验证这些签名 在两个不同的位置进行重复性测试，随后将评估6个临床样本 审判。开发这些分析所必需的临床样本和数据将从两个主要的 国际PTCL项目(IP-PTCL)与淋巴瘤和白血病分子 为GEP研究提供了标本和临床数据的LLMPP。其他内容 各机构将参与为验证研究提供新的案例。我们具有得天独厚的优势 要完成这项工作，就得出这些疾病的“黄金标准”诊断和预后信号 淋巴瘤，以及有匹配的新鲜冰冻组织和FFPET块。我们组使用了一种 用类似的方法开发“Lymph2Cx”试验，以便在GCB和ABC之间进行强有力的区分 弥漫性大B细胞淋巴瘤亚型。

Abstract Peripheral T-cell lymphomas (PTCL) represent approximately 10-12% of all NHL in the western world and generally exhibit poor prognosis with standard chemotherapy. Another significant challenge is that using current diagnostic approaches, approximately 30-50% of PTCL cases cannot be assigned to a specific entity and are categorized as PTCL-not otherwise specified (PTCL-NOS). Of the more common PTCL entities recognized by WHO classification, we have defined robust molecular gene expression signatures that can differentiate the five PTCLs entities: angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase positive anaplastic large-cell lymphoma (ALK(+)ALCL), ALK-negative anaplastic large-cell lymphoma (ALK(-)ALCL), adult T-cell leukemia/lymphoma (ATLL), and extranodal natural killer/T-cell lymphoma (ENKTCL). PTCL-NOS can now be separated into two distinct molecular subgroups (the TBX21 and GATA3 subgroups). A prognostic model for AITL has also been developed. Overall, these represent more than 80% of all the PTCL. The aim of this proposal is to consolidate these diagnostic and prognostic signatures into a single technology platform that can be applied to formalin fixed, paraffin embedded tissues (FFPET) to improve standardization and accuracy of PTCL diagnosis. This platform will be applicable to not only routine clinical applications, but will help to stratify patients in prospective clinical trials for new therapeutic agents. We will validate these signatures in a CLIA setting at two different locations for reproducibility and will subsequently evaluate specimens from six clinical trials. Clinical samples and data essential to develop these assays will be obtained from the two major consortiums: the International PTCL Project (IP-PTCL) and the Lymphoma and Leukemia Molecular Profiling Project (LLMPP), which had provided specimens and clinical data for the GEP study. Additional institutions will participate to provide new cases for validation studies. We are uniquely positioned to accomplish this work by having derived the “gold standard” diagnostic and prognostic signatures of these lymphomas, as well as having matching fresh frozen tissue and FFPET blocks. Our group has used a similar approach to develop the “Lymph2Cx” assay for a robust distinction between the GCB and ABC subtype of diffuse large B-cell lymphoma.