Genetic Predictors of Early Clinical Failure in Diffuse Large B Cell Lymphoma

项目摘要/摘要 弥漫性大B细胞淋巴瘤(DLBCL)占所有新诊断的非霍奇金淋巴瘤的近40% 淋巴瘤(NHL)在美国目前，主要用临床因素来识别高或低 风险患者和预测总存活率，但实用性不大。我们最近已经证明， 接受以蒽环类药物为基础的免疫化疗的新诊断患者(护理标准) 在确诊后24个月内没有疾病进展或复发、再次治疗或死亡的患者 (称为无事件生存或EFS24)DLBCL的患者有正常的预期寿命，而 未能实现这一标志性的哨兵有非常糟糕的结果。虽然我们已经确定了临床 这些终点的预测因素，我们假设体细胞(肿瘤)和生殖系(宿主)基因 生物标志物可以提高我们在诊断时预测哪些患者将出现早期临床的能力 失败，并有助于确定新的生物学和治疗方法。我们来自全食超市的初步数据- DLBCL患者的外显子组测序和全基因组相关性研究表明，存在 预测EFS24失败的体细胞和生殖系遗传生物标志物，以及这些 与已知的驱动因素和易感基因不同。根据这些研究结果，我们建议 具体目标如下：1)识别、验证和临床翻译体细胞遗传生物标记物 未能达到EFS24；2)识别、验证和临床翻译生殖系基因 未能达到EFS24的生物标志物；以及3)开发和验证一个综合模型，该模型 将体细胞和生殖系遗传生物标志物与临床预后因素相结合。对于每个目标，我们 还将通过使用生物信息学工具初步评估生物标记物的功能，以及何时 适用，在模型系统中进行初始实验室审问。我们将使用 梅奥诊所和爱荷华州大学淋巴瘤医院的广泛资源 卓越研究专项计划(孢子)和淋巴瘤流行病学成果 (LEO)队列，并与Lysa(法国淋巴瘤试验小组)和 梅奥诊所检验医学和病理学系。我们预计，我们的结果将 通过导致宿主和宿主的临床翻译对DLBCL的管理产生重大影响 肿瘤遗传生物标记物用于风险分层，识别可能受益的高危患者 更密集的治疗或非标准的一线药物方案，以及新生物的鉴定 和治疗靶点。

PROJECT SUMMARY/ABSTRACT Diffuse large B cell lymphoma (DLBCL) compromises nearly 40% of all newly diagnosed non-Hodgkin lymphomas (NHL) in the U.S. Currently, mainly clinical factors are used to identify high versus low risk patients and to predict overall survival, but with modest utility. We have recently shown that newly diagnosed patients treated with anthracycline-based immunochemotherapy (standard of care) who do not have disease progression or relapse, retreatment, or death within 24 months of diagnosis (termed event-free survival or EFS24) for DLBCL have a normal life expectancy, while patients who fail to achieve this sentinel landmark have very poor outcomes. While we have identified clinical predictors of these endpoints, we hypothesize that both somatic (tumor) and germline (host) genetic biomarkers can improve our ability to predict at diagnosis which patients will have an early clinical failure and help identify novel biology and therapeutic approaches. Our preliminary data from whole- exome sequencing and genome-wide association studies in DLBCL patients suggests that there are both somatic and germline genetic biomarkers that predict failure to achieve EFS24, and that these are different from known drivers and susceptibility loci. Building on these findings, we propose the following specific aims are: 1) To identify, validate and clinically translate somatic genetic biomarkers for failure to achieve EFS24; 2) To identify, validate, and clinically translate germline genetic biomarkers for failure to achieve EFS24; and 3) To develop and validate an integrative model that combines somatic and germline genetic biomarkers with clinical prognostic factors. For each aim, we will also initially assess biomarker function through the use of bioinformatics tools, and when applicable, with initial laboratory interrogation in model systems. We will address our aims using the established and extensive resources of the Mayo Clinic and University of Iowa Lymphoma Specialized Program of Research Excellence (SPORE) and Lymphoma Epidemiology of Outcomes (LEO) cohort, and established collaborations with the LYSA (French Lymphoma Trials Group) and the Mayo Clinic Department of Laboratory Medicine and Pathology. We anticipate that our results will have a major impact on the management of DLBCL by leading to clinical translation of both host and tumor genetic biomarkers for risk stratification, identifying high-risk patients who might benefit from more intensive therapies or non-standard first-line drug regimens, and identification of novel biology and therapeutic targets.