Molecular diagnostic and prognostic signatures for PTCL

PTCL 的分子诊断和预后特征

• 批准号: 10017897
• 负责人: Wing C. Chan
• 金额: $ 30.1万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017897
• 关键词: Adult T-Cell Leukemia/Lymphoma; Biological Assay; Biological Markers; Biopsy; Categories; Classification; Clinical; Clinical Data; Clinical Laboratory Improvement Amendments; Clinical Trials; Complex; Custom; Cytotoxic T-Lymphocytes; Data; Diagnosis; Diagnosis Clinical Trials; Diagnostic; Disease; Exhibits; Extranodal; Formalin; Freezing; Future; GATA3 gene; Gene Expression Profile; Gene Expression Profiling; Gold; Immunoblastic Lymphadenopathy; Immunophenotyping; Institution; International; Investigation; Ki-1 Large-Cell Lymphoma; Laboratories; Location; Lymphoma; Molecular; Molecular Profiling; Morphology; Neoplasms; Paraffin Embedding; Pathologic; Patients; Performance; Peripheral; Positioning Attribute; Reproducibility; Sampling; Specific qualifier value; Specimen; Standardization; Subgroup; System; T-Cell Lymphoma; Technology; Therapeutic Agents; Tissue Embedding; Tissues; Transcript; Translating; Validation; Western World; Work; anaplastic lymphoma kinase; chemotherapy; clinical Diagnosis; clinical application; clinical practice; diagnostic assay; genetic signature; improved; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; molecular diagnostics; nano-string; novel; novel therapeutics; outcome forecast; patient stratification; predictive modeling; prognostic; prognostic signature; prognostic significance; prognostic value; prospective; response; specific biomarkers; validation studies

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.

抽象的 周围T细胞淋巴瘤（PTCL）约占西方世界所有NHL的10-12％ 并且通常通过标准化疗暴露了预后不良。另一个重大挑战是 使用当前的诊断方法，大约30-50％的PTCL病例无法分配给 特定实体，并将其归类为PTCL-NOT另有指定（PTCL-NOS）。更常见的 由WHO分类识别的PTCL实体，我们定义了可靠的分子基因表达 可以区分五个PTCL实体的签名：血管免疫细胞T细胞淋巴瘤（AITL）， 层状淋巴瘤​​激酶阳性偏长型大细胞淋巴瘤（ALK（+）ALCL），ALK阴性 塑性大细胞淋巴瘤（ALK（ - ）ALCL），成人T细胞白血病/淋巴瘤（ATLL）和外道 天然杀伤/T细胞淋巴瘤（ENKTCL）。 PTCL-NOS现在可以分为两个不同的分子 亚组（TBX21和GATA3亚组）。还开发了AITL的原型模型。 总体而言，这些占所有PTCL的80％以上。该提议的目的是巩固这些 诊断和预后签名到一个可以应用于福尔马林的单个技术平台 固定的石蜡嵌入组织（FFPET）以提高PTCL诊断的标准化和准确性。 该平台将不仅适用于常规临床应用，而且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环境中验证这些签名 在两个不同的位置可重现性，随后将评估六个临床的标本 试验。开发这些测定必不可少的临床样本和数据将从两个主要的 财团：国际PTCL项目（​​IP-PTCL）以及淋巴瘤和白血病分子 分析项目（LLMPP）为GEP研究提供了标本和临床数据。额外的 机构将参加验证研究的新案例。我们是独特的位置 通过得出这些工作的“黄金标准”诊断和预后签名来完成这项工作 淋巴瘤，并具有匹配的新鲜冷冻组织和FFPET块。我们的小组使用了 类似的方法来开发“淋巴2CX”测定法，以在GCB和ABC之间进行牢固区分 扩散大B细胞淋巴瘤的亚型。