Molecular Diagnosis and Prognosis in Aggressive Lymphoma

描述（由申请人提供）：本申请是根据PAR-10-126，癌症特征评估战略合作[SPECS II] （U01）编写的。拟议的项目重点是将我们以前的发现导向的基因表达特征转化为淋巴瘤临床试验和患者护理的实验室测试。我们的研究联盟淋巴瘤和白血病分子分析项目（LLMPP）将设计并验证一种多分析物诊断和预后基因标记试验，以区分5种最常见的侵袭性B细胞非霍奇金淋巴瘤。然后将每个淋巴瘤亚型进一步划分为预后组。在我们的可行性测试中，我们将严格评估高密度寡核苷酸阵列（Affymetrix）、基因表达的直接多路测量（Nanostring）和定量核酸酶保护测定（high Throughput Genomics）等三种基因表达谱分析方法。在第一阶段，诊断基因将在所有3个平台上进行测试，同时在NCI-Frederick的患者特征中心（PCC）进行比较，该中心由SAIC-Frederick和第二个学术研究中心运营。在第二阶段，“获胜”的平台将在PCC和另外两个站点进行测试。在第二阶段，测试的基因将扩大到包括预后特征。数据将以适合提交监管审查的方式生成。与我们之前使用快速冷冻组织的发现工作不同，该项目将使用福尔马林固定的石蜡包埋组织（FFPET），这是所有活组织检查中常规使用的，以获得最广泛的临床应用。LLMPP是唯一能够完成这项工作的，因为它已经完成了“金标准”GEP实验，定义了这些淋巴瘤的诊断和预后区别，并保存了来自相同病例的匹配FFPET块。因此，本文提出的研究解决了一个关键的未满足的需求，即将先前在侵袭性淋巴瘤分子诊断方面的进展转化为准确诊断、预后和治疗靶点识别的新临床范例。

DESCRIPTION (provided by applicant): This application is written in response to PAR-10-126, Strategic Partnering to Evaluate of Cancer Signatures [SPECS II] (U01)." The proposed project focuses on translating our previously discovery-oriented gene expression signatures into laboratory tests for lymphoma clinical trials and patient care. Our research consortium, the Lymphoma and Leukemia Molecular Profiling Project (LLMPP) will design and validate a multi-analyte diagnostic and prognostic gene signature assay to differentiate the 5 most common aggressive B cell non-Hodgkin lymphomas. Each lymphoma subtype will then be further classified into prognostic groups. Three methods of gene expression profiling with demonstrated utility in our feasibility testing will be rigorously evaluated including high density oligonucleotide arrays (Affymetrix), direct multiplexed measurement of gene expression (Nanostring), and quantitative nuclease protection assay (High Throughput Genomics). In Phase 1 diagnostic genes will be tested at all 3 platforms will be compared simultaneously at the Patient Characterization Center (PCC) at NCI-Frederick, operated by SAIC-Frederick and a second academic study site. In Phase 2, the "winning" platform will be tested at the PCC and 2 additional sites. In Phase 2, tested genes will be expanded to include prognostic signatures. Data will be generated in such a way as to be appropriate for submission for regulatory review. As opposed to our previous discovery work that was performed with snap frozen tissues which are scare and only available at academic centers, this project will use formalin fixed, paraffin embedded tissues (FFPET), which are routinely available from all biopsies, in order to have the broadest clinical application. The LLMPP is uniquely posed to accomplish this work by virtue of having performed the "gold standard" GEP experiments that define the diagnostic and prognostic distinctions in these lymphomas as well as holding matching FFPET blocks from the same cases. Hence, this proposed research addresses a critical unmet need to translate previous advances in the molecular diagnosis of aggressive lymphomas into a new clinical paradigm for accurate diagnosis, prognosis, and therapeutic target identification.