Molecular Diagnosis, Prognosis, and Therapeutic Targets in Lymphoma

本申请是代表淋巴瘤和白血病分子图谱项目(LLMPP)提交的，该项目是 总部设在美国的长期、紧密整合的国际研究联盟，具有高度的 发现和临床翻译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个赠送项目 为了扩大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)，(2)外套细胞淋巴瘤(Campo博士)，(3)外周T细胞淋巴瘤(Iqbal博士)，以及(4)间变性 大细胞淋巴瘤(费尔德曼博士)。整体研究策略将扩展我们的基因表达 对更大更全面的基因组学分析的表征和初步测序研究 (包括序列、重排、拷贝数变化和表观遗传学)，以确定新的 具有独特生物学特征、预后和治疗目标的诊断类别。在侵袭性B细胞中 淋巴瘤迫切需要了解与之相关的适当诊断分类 治疗失败。由于生长缓慢，套细胞淋巴瘤的预后千差万别 肿瘤需要对需要移植的人进行最小限度的治疗，因此可能代表不止一个 疾病。外周T细胞淋巴瘤--没有特殊说明是一种几乎是孤儿的疾病，患者寥寥无几 尽管接受了激烈的治疗，但仍能活下来。间变性大细胞淋巴瘤是一种罕见的疾病，预后不一。 成人和儿童的基因不同。这些项目的细节在附加摘要中进行了描述。我们 总体而言，侵袭性B细胞和T细胞淋巴瘤可以通过基因组进一步细分 改变包括易位伙伴、断裂点、突变、拷贝数改变、 表观遗传学和表型，这些特征可以从功能上表征并用于 改善患者护理。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患者初级组织活检的分析 准确的诊断、质量和肿瘤内容。这笔赠款的个别科学项目将通过以下方式协同 共享组织、科学策略、数据、分析技术和分析开发专业知识。这 团队合作将得到功能基因组学和患者来源的肿瘤移植系统的赞扬 临床建模。这些项目将与生物统计学密切合作，以进行研究设计、分析和使用 生物信息学来分析高通量数据。因此，拟议的核心包括行政(DR)。 Rimsza)、病理学(Cook博士)、功能基因组学(Staudt博士)、临床前模型和治疗学(Dr. Inghirami)和生物统计与生物信息学(Dr.Wright)。总体意图是将基因组研究作为一种 更好地了解疾病生物学，制定更正确的分类和预后，并识别 并确定治疗目标；以提高患者存活率为长期目标。

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.