Molecular diagnostic and prognostic signatures for PTCL

摘要 外周T细胞淋巴瘤（PTCL）约占西方国家所有NHL的10- 12 并且通常用标准化疗表现出不良预后。另一个重大挑战是， 使用目前的诊断方法，大约30-50%的PTCL病例不能被分配到一个 特定实体，并归类为PTCL-未另行说明（PTCL-NOS）。比较常见的 PTCL实体被WHO分类认可，我们定义了稳健的分子基因表达 可以区分五种PTCL实体的特征：血管免疫母细胞性T细胞淋巴瘤（AITL）， 间变性淋巴瘤激酶阳性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）和淋巴结转移 自然杀伤/T细胞淋巴瘤（ENKTCL）。PTCL-NOS现在可以分为两个不同的分子 亚组（TBX 21和GATA 3亚组）。还开发了一个AITL的预测模型。 总体而言，这些占所有PTCL的80%以上。这项建议的目的是巩固这些 将诊断和预后特征整合到一个单一的技术平台中， 固定的石蜡包埋组织（FFPET），以提高PTCL诊断的标准化和准确性。 该平台不仅适用于常规临床应用，还将有助于对患者进行分层， 新治疗药物的前瞻性临床试验。我们将在CLIA设置中验证这些签名 在两个不同的地点进行重现性研究，随后将对来自六个临床 审判开发这些检测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）和淋巴瘤和白血病分子 分析项目（LLMPP），该项目为GEP研究提供了标本和临床数据。额外 各机构将参与，为验证研究提供新的案例。我们有独特的优势， 完成这项工作，通过推导出“金标准”的诊断和预后的签名，这些 淋巴瘤，以及具有匹配的新鲜冷冻组织和FFPET块。我们的团队使用了 开发“Lymph 2Cx”检测试剂盒的类似方法，用于稳健区分GCB和ABC 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.