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

弥漫性大 B 细胞淋巴瘤早期临床失败的遗传预测因素

基本信息

批准号：
9380363
负责人：
JAMES R CERHAN
金额：
$ 66.76万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9380363
关键词：
Address Aftercare Anthracyclines Bioinformatics Biological Markers Biological Models Biology Cessation of life Clinic Clinical Cohort Studies Collaborations Data Data Discovery Diagnosis Disease Progression Disease-Free Survival Epidemiology Failure Genetic Genetic Markers Genomics Geography Goals International Prognostic Index Iowa Laboratories Life Expectancy Lymphoma Medicine Modeling Newly Diagnosed Non-Hodgkin&apos s Lymphoma Outcome Pathology Patient risk Patients Pharmaceutical Preparations Prognostic Factor Regimen Relapse Resources Retreatment Risk Risk stratification Sentinel Specialized Program of Research Excellence Susceptibility Gene Therapeutic Translating Tumor Biology Universities Variant Work base cancer immunotherapy clinical epidemiology clinical predictors clinical translation clinically actionable cohort comparative genomic hybridization ethnic diversity exome exome sequencing follow-up genetic epidemiology genetic predictors genome wide association study high risk improved innovation large cell Diffuse non-Hodgkin&apos s lymphoma next generation sequencing novel predictive marker racial and ethnic standard of care therapeutic target tool tumor whole genome

项目摘要

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.

项目概要/摘要近 40% 的新诊断非霍奇金淋巴瘤患者患有弥漫性大 B 细胞淋巴瘤 (DLBCL) 在美国，淋巴瘤 (NHL) 目前主要使用临床因素来识别高与低风险患者并预测总体生存率，但实用性不大。我们最近表明新诊断的患者接受基于蒽环类的免疫化疗（标准护理）诊断后 24 个月内没有疾病进展或复发、再治疗或死亡的人 DLBCL（称为无事件生存期或 EFS24）的患者预期寿命正常，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这些终点的预测因子，我们假设体细胞（肿瘤）和种系（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有早期临床症状的能力失败并帮助确定新的生物学和治疗方法。我们的初步数据来自整个 DLBCL 患者的外显子组测序和全基因组关联研究表明，预测无法达到 EFS24 的体细胞和种系遗传生物标志物，并且这些与已知的驱动因素和易感性位点不同。基于这些发现，我们提出以下具体目标是： 1) 识别、验证和临床转化体细胞遗传生物标志物未能达到 EFS24； 2) 识别、验证和临床转化种系遗传未达到 EFS24 的生物标志物； 3) 开发并验证一个综合模型将体细胞和种系遗传生物标志物与临床预后因素结合起来。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，以及何时适用，并在模型系统中进行初步实验室询问。我们将通过以下方式实现我们的目标：梅奥诊所和爱荷华大学淋巴瘤中心的成熟且广泛的资源卓越研究专业计划 (SPORE) 和淋巴瘤流行病学结果 (LEO) 队列，并与 LYSA（法国淋巴瘤试验组）和梅奥诊所检验医学和病理学部。我们预计我们的结果将通过导致宿主和 DLBCL 的临床转化，对 DLBCL 的治疗产生重大影响用于风险分层的肿瘤遗传生物标志物，识别可能受益的高风险患者更强化的治疗或非标准一线药物治疗方案，以及新生物学的鉴定和治疗目标。