Molecular Diagnosis, Prognosis, and Therapeutic Targets in Lymphoma

本申请是代表淋巴瘤和白血病分子特征分析项目（LLMPP）提交的， 长期以来，紧密结合，国际研究财团总部设在美国，具有高度的 发现和临床转化的成功记录深刻地影响了已知的生物学， 淋巴瘤的分类和治疗。在目前的申请中，我们提出了4个免费项目 为了扩展我们对难以治疗的淋巴瘤的理解，包括（1）侵袭性B细胞淋巴瘤（Dr. Scott博士），（2）套细胞淋巴瘤（Campo博士），（3）外周T细胞淋巴瘤（Iqbal博士），和（4）间变性淋巴瘤 大细胞淋巴瘤（Feldman博士）。整个研究策略将扩展我们的基因表达 将基因组学的表征和初始测序研究转化为更大更全面的分析 （包括序列、重排、拷贝数变异和表观遗传学），以鉴定新的 具有独特的生物学特征、代谢和治疗靶点的诊断类别。在侵袭性B细胞中 淋巴瘤有一个迫切需要了解适当的诊断分类， 治疗失败。套细胞淋巴瘤有一个非常可变的结果范围从缓慢增长的 需要最少治疗的肿瘤与需要移植的肿瘤相比，因此可能代表不止一种 疾病外周T细胞淋巴瘤-未另行说明是一种几乎罕见的疾病， 尽管接受了高强度治疗但仍存活了下来间变性大细胞淋巴瘤是一种罕见的疾病， 不同的基因。这些项目的详细情况见其他摘要。我们 总体假设侵袭性B和T细胞淋巴瘤可以通过基因组进一步细分， 改变，包括易位伴侣、断裂点、突变、拷贝数改变， 表观遗传学和表型，这些特征可以在功能上表征并用于 改善病人护理。正如我们之前的工作一样，这些翻译项目的基础将是复杂的 由病理学家小组共同审查的来自患者的原发性组织活检的分析， 准确诊断、质量和肿瘤内容。该补助金的各个科学项目将通过以下方式发挥协同作用： 共享组织、科学策略、数据、分析技术和检测开发专业知识。这 团队合作将得到功能基因组学和患者来源的肿瘤异种移植系统的补充， 临床建模这些项目将与生物统计学密切合作，进行研究设计、分析和使用 生物信息学分析高通量数据。因此，拟议的核心包括行政（博士。 Rimsza）、病理学（Cook博士）、功能基因组学（施陶德博士）、临床前模型和治疗学（Dr. Inghirami）和生物统计学和生物信息学（赖特博士）。总的目的是利用基因组研究作为 平台，以更好地了解疾病生物学，制定更正确的分类和预后， 并表征治疗靶点;长期目标是提高患者生存率。

This application is submitted on behalf of the Lymphoma and Leukemia Molecular Profiling Project (LLMPP), a long-standing, tightly integrated, international research consortium based in the United States with a highly successful track-record of discovery and clinical translation profoundly impacting the known biology, classification, and treatment of lymphoma. In the current application, we propose 4 complimentary projects to extend our understanding of difficult to treat lymphomas including (1) Aggressive B cell lymphomas (Dr. Scott), (2) Mantle cell lymphoma (Dr. Campo), (3) Peripheral T cell lymphoma (Dr. Iqbal), and (4) Anaplastic large cell lymphoma (Dr. Feldman). The overall research strategy will extend our gene expression characterization and initial sequencing studies into larger more comprehensive analyses of genomics (including sequence, rearrangements, copy number variations, and epigenetics) in order to identify new diagnostic categories with unique biological features, prognoses, and therapeutic targets. In Aggressive B cell lymphomas there is a pressing need to understand the appropriate diagnostic categorization as related to treatment failure. Mantle cell lymphoma has an extremely variable range of outcomes from slow growing tumors requiring minimal therapy to those requiring transplant and thus likely represents more than one disease. Peripheral T cell lymphoma-Not otherwise specified is a nearly orphan disease with few patients surviving despite intense therapy. Anaplastic large cell lymphoma is a rare disease with variable outcome and different genetics in adults versus children. The Projects' details are described in additional abstracts. We overall hypothesize that aggressive B and T cell lymphomas can be further subdivided by genomic alterations including translocation partners, breakpoints, mutations, copy number alterations, epigenetics, and phenotype and that these features can be functionally characterized and used to improve patient care. As in our prior work, the bedrock of these translational projects will be sophisticated analyses of primary tissue biopsies from patients that are communally reviewed by a panel of pathologists for accurate diagnosis, quality, and tumor content. The individual scientific projects of this grant will synergize by sharing tissues, scientific strategies, data, analysis techniques, and assay development expertise. This teamwork will be complimented by functional genomics and patient derived tumor xenograft systems for pre- clinical modeling. The Projects will work closely with biostatistics for study design and analysis and use bioinformatics to analyze high throughput data. Thus, the proposed cores include Administrative (Dr. Rimsza), Pathology (Dr. Cook), Functional Genomics (Dr. Staudt), Preclinical Models and Therapeutics (Dr. Inghirami) and Biostatistics & Bioinformatics (Dr. Wright). The overall intention is to use genomic studies as a platform to better understand disease biology, develop more correct classification and prognosis, and identify and characterize therapeutic targets; with a long-term goal of enhancing patient survival.