Project 4: Genomic Predictors of Early Relapse in Immunochemotherapy-Treated Follicular Lymphoma

摘要：项目4。滤泡性淋巴瘤（FL）是最常见的惰性非霍奇金淋巴瘤， 有高度可变的临床过程。无症状和低肿瘤负荷患者最初可通过以下方式进行管理： 观察或利妥昔单抗单药治疗，而症状性和高肿瘤负荷患者通常 在诊断时使用免疫化疗（IC）作为标准治疗进行管理。我们已经表明，IC处理的FL 实现无事件的患者（即，无疾病进展或再次治疗）状态 诊断（EFS 24）有随后的预期寿命的背景年龄和性别匹配的一般 而那些未能达到EFS 24的人患有预后不良的侵袭性疾病。之一 对于新的以国家信息中心为驱动的外语发展范例来说，最优先的任务是解决外语的早期事件，包括 了解潜在的生物学，识别预后和预测标志物，并最终开发 为这些患者提供新的治疗靶点和管理策略。我们假设一部小说 生殖系（宿主）和体细胞（肿瘤）基因组生物标志物、肿瘤基因表达和临床 这些因素，可以提高我们在诊断时预测哪些IC治疗的FL患者将有早期临床症状的能力。 失败，定义为未能达到EFS 24。为了验证这一假设，我们建议识别，验证和 临床翻译生殖系遗传生物标志物（Aim 1）、体细胞肿瘤基因组生物标志物（Aim 2）和基因 表达签名（目标3）未能达到EFS 24在IC处理的FL，然后开发和验证一个 一种新的综合模型（Aim 4），将临床预后因素与从 目标1-3。为了实现这些目标，我们组建了一支优秀的跨学科团队， 在拟议的研究中的专业知识。该研究利用淋巴瘤孢子的既定资源， 我们的横向合作（LLMPP，SWOG，LYSA），以及我们在淋巴瘤流行病学的领导地位， 结局（LEO）队列。我们的创新人口科学项目将是第一个全面 发现和验证生殖系遗传、肿瘤基因组和基因表达生物标志物，以避免未能实现 EFS24。我们设计了具有高内部效度的研究，重点是使用大型患者队列 高质量的生物样本、临床和结果数据;生物样本处理的广泛质量控制 和分析;以及对结果进行外部验证的多阶段研究，包括使用地理和 来自LEO队列研究的IC治疗FL患者的种族/种族多样性样本，这也增强了 我们的结果的普遍性。我们全面的发现-验证和临床翻译方法 应该产生一个可靠的，多参数的，预后模型，对管理的重大影响的潜力 的IC治疗FL患者的最终目标是准确，个性化的患者管理以及新的 深入了解淋巴瘤生物学，也可以帮助识别治疗靶点。

ABSTRACT: Project 4. Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and has a highly variable clinical course. Asymptomatic and low-tumor burden patients can initially be managed by observation or rituximab-monotherapy, while symptomatic and high-tumor burden patients are typically managed at diagnosis with immunochemotherapy (IC) as standard of care. We have shown that IC-treated FL patients who achieve event-free (i.e., no disease progression or re-treatment) status at 24 months after diagnosis (EFS24) have the subsequent life expectancy of the background age and sex matched general population, while those who fail to achieve EFS24 have aggressive disease with poor outcomes. One of the highest priorities for the new NCI-driven paradigm for progress in FL is to address early events in FL including understanding the underlying biology, identifying prognostic and predictive markers, and ultimately developing new therapeutic targets and management strategies for these patients. We hypothesize that a novel combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors, can improve our ability to predict at diagnosis which IC-treated FL patients will have an early clinical failure, defined as failure to achieve EFS24. To test this hypothesis, we propose to identify, validate and clinically translate germline genetic biomarkers (Aim 1), somatic tumor genomic biomarkers (Aim 2), and gene expression signatures (Aim 3) for failure to achieve EFS24 in IC-treated FL and then develop and validate a novel integrative model (Aim 4) that combines clinical prognostic factors with the biomarkers identified from Aims 1-3. To address these aims, we have assembled an outstanding interdisciplinary team with extensive expertise in the proposed studies. The study leverages the established resources of the Lymphoma SPORE, our horizontal collaborations (LLMPP, SWOG, LYSA), and our leadership in the Lymphoma Epidemiology of Outcomes (LEO) cohort. Our innovative population science project will be the first to comprehensively discover and validate germline genetic, tumor genomic, and gene expression biomarkers for failure to achieve EFS24. We have designed studies that have high internal validity, with a focus on use of large patient cohorts with high quality biospecimens, clinical and outcome data; extensive quality control in biologic sample handling and assays; and multi-stage studies with external validation of results, including use of a geographically and racially/ethnically diverse sample of IC-treated FL patients from the LEO cohort study, which also enhances the generalizability of our results. Our comprehensive approach of discovery-validation and clinical translation should yield a reliable, multiparameter, prognostic model, with potential for major impact on the management of IC-treated FL patients with the ultimate goal of accurate, personalized patient management as well as new insights into lymphoma biology that can also aid in identification of therapeutic targets.