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 外周 T 细胞淋巴瘤 (PTCL) 约占西方国家所有 NHL 的 10-12% 另一个重大挑战是标准化疗通常表现出不良预后。 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，并归类为 PTCL-未另行指定 (PTCL-NOS)。 WHO分类认可的PTCL实体，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 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) 和结外 自然杀伤/T 细胞淋巴瘤 (ENKTCL) 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 的预后模型。 总体而言，这些占所有 PTCL 的 80% 以上。本提案的目的是巩固这些。 将诊断和预后特征集成到可应用于福尔马林的单一技术平台中 固定石蜡包埋组织 (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 我们将在 CLIA 环境中验证这些新治疗药物的前瞻性临床试验。 在两个不同的地点进行重复性测试，随后将评估来自六个临床的样本 开发这些检测所必需的临床样本和数据将从两个主要项目中获得。 联盟：国际 PTCL 项目 (IP-PTCL) 和淋巴瘤和白血病分子学会 分析项目 (LLMPP)，为 GEP 研究提供了样本和临床数据。 机构将参与提供新的验证研究案例。 通过得出这些的“黄金标准”诊断和预后特征来完成这项工作 淋巴瘤，以及新鲜冷冻组织和 FFPET 块。 类似的方法来开发“Lymph2Cx”检测，以明确区分 GCB 和 ABC 弥漫性大 B 细胞淋巴瘤的亚型。