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

项目概要/摘要 弥漫性大B细胞淋巴瘤（DLBCL）占所有新诊断非霍奇金淋巴瘤的近40 目前，主要的临床因素被用来识别高与低的淋巴瘤。 风险患者，并预测总生存期，但具有适度的效用。我们最近的研究表明 接受基于蒽环类药物的免疫化疗（标准治疗）的新诊断患者 在诊断后24个月内未发生疾病进展或复发、重新治疗或死亡的患者 DLBCL的无事件生存期（称为EFS 24）具有正常的预期寿命，而 未能实现这一标志性里程碑的结果非常糟糕。虽然我们已经确定了临床 作为这些终点的预测因子，我们假设体细胞（肿瘤）和生殖系（宿主）遗传 生物标志物可以提高我们在诊断时预测哪些患者将具有早期临床症状的能力。 失败和帮助确定新的生物学和治疗方法。我们的初步数据来自- DLBCL患者的外显子组测序和全基因组关联研究表明， 体细胞和种系遗传生物标志物，预测未能实现EFS 24，这些 与已知的驱动基因和易感基因座不同。基于这些发现，我们建议 以下具体目标是：1）鉴定、验证和临床翻译体细胞遗传生物标志物 2）鉴定、验证和临床翻译生殖系遗传学， 未能实现EFS 24的生物标志物;和3）开发和验证一个综合模型， 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。对于每一个目标，我们 还将通过使用生物信息学工具初步评估生物标志物功能， 适用，在模型系统中进行初步实验室询问。我们将使用 马约诊所和爱荷华州大学淋巴瘤的建立和广泛的资源 卓越研究的专业计划（SPORE）和淋巴瘤流行病学的结果 (LEO)队列，并与LYSA（法国淋巴瘤试验组）和 马约诊所实验室医学和病理学部门。我们预计，我们的结果将 对DLBCL的管理产生重大影响，导致宿主和 用于风险分层的肿瘤遗传生物标志物，识别可能受益于 更强化的治疗或非标准的一线药物方案，以及新生物学的鉴定 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.