Risk factors for molecular subtypes of NHL a prospective evaluation

NHL 分子亚型的危险因素前瞻性评估

• 批准号: 9306035
• 负责人: BRENDA M BIRMANN
• 金额: $ 83万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306035
• 关键词: Address; Adult; Alcohol consumption; Alcohols; Archives; B-Cell Lymphomas; BCL2 gene; Behavioral; Body mass index; California; Cancer Prevention Study II; Case Study; Case-Control Studies; Cells; Characteristics; Chronic; Clinical; Clinical Distribution; Cohort Studies; Collaborations; Controlled Study; Data; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Progression; Enrollment; Epidemiology; Etiology; Evaluation; Exposure to; Fibrinogen; Follicular Lymphoma; Follow-Up Studies; Formalin; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Health Professional; Heterogeneity; Histologic; Immune response; Immunization; Immunohistochemistry; Individual; Infection; Inflammation; Knowledge; Lead; Link; Lymphoma; Malignant Neoplasms; Measures; Menopause; Methodology; Molecular; Molecular Profiling; Mutation; Non-Hodgkin' s Lymphoma; Nurses' Health Study; Paraffin Embedding; Population; Population Attributable Risks; Prospective cohort study; Prothrombin; Reporting; Research; Research Design; Research Personnel; Retrieval; Risk; Risk Estimate; Risk Factors; Role; Series; Smoking; Source; Standardization; Structure of germinal center of lymph node; Study Subject; Sun Exposure; Time; Tissue Banks; Tissue Embedding; Tissues; Translations; Tumor Subtype; Tumor Tissue; United States; Validation; Variant; Weight; World Health Organization; base; case control; cigarette smoking; clinically relevant; cohort; epidemiology study; hormone therapy; large cell Diffuse non-Hodgkin' s lymphoma; modifiable risk; molecular subtypes; outcome forecast; prospective; protein expression; teacher; tumor; young adult

ABSTRACT In this application, we aim to directly address key gaps in our knowledge of NHL etiology and promote “best practices” for future research. NHL etiologic research has largely been driven by pooled case-control studies, which have suggested a number of modifiable risk factors, but which also (i) may be influenced by unmeasured biases (survival, recall); (ii) cannot inform calculation of population attributable risk (ARp%); and (iii) have been limited by the lack of available tumor tissue for delineating molecular subtypes. Our study objective is to evaluate purported NHL risk factors using a pooled analysis of over 500,000 individuals followed for ~20 years from five cohort studies with >5000 incident NHLs. These cohorts have: (i) detailed longitudinal information on common modifiable risk factors queried in a similar manner over a similar period of time, and (ii) active tumor tissue collection efforts. In Aim 1, we will conduct a pooled time-dependent analysis in the prospective cohort studies to evaluate NHL risk factors consistently reported in case-control studies, assess the importance of exposure timing, and calculate the ARp% of confirmed risk factors. Specifically, we will evaluate five key purported modifiable risk factors: (i) young and usual adult body mass index (BMI); (ii) alcohol; (iii) sun exposure, (iv) smoking, and (v) menopausal hormone therapy; and two emerging risk factors of relevance to the immune response: (i) diabetes and (ii) chronic infections. In Aim 2, we will characterize and evaluate the importance of tumor molecular characteristics to these etiologic associations and ARp%. Specifically, unique gene expression patterns linked to survival in diffuse large B-cell lymphoma (DLBCL) and distinct gene mutations that denote disease progression in follicular lymphoma (FL) have been identified. “Double hit” lymphomas have also been shown to have poor prognosis among multiple lymphoma subtypes. New multi-analyte gene expression assays developed for formalin-fixed paraffin-embedded tissues now make the delineation of these unique molecular signatures in epidemiologic studies possible. Because tissues archived from epidemiologic studies reflect only a subset of all cases, we will compare the epidemiologic and clinical characteristics of tissues retrieved from cohort studies to an unbiased series of tissues from Kaiser Permanente Southern California. This comparison will permit us to quantify survival bias in case-control study findings and potential bias in tissue ascertainment in the cohort-related tissues. The quantification of these biases in case ascertainment and tissue retrieval will enable us to interpret resulting Aim 1 risk associations and adjust ARp% calculations accordingly.

抽象的 在此应用中，我们旨在直接解决我们对NHL病因的知识中的关键差距并促进 未来研究的“最佳实践”。 NHL病因研究在很大程度上是由汇总的病例对照驱动的 研究提出了许多可修改的危险因素，但也可能受到（i）的影响 未衡量的偏见（生存，召回）； （ii）无法告知人口归因风险的计算（ARP％）；和 （iii）由于缺乏可用的肿瘤组织来描述分子亚型。我们的研究 目的是使用超过500,000个人的汇总分析评估所谓的NHL风险因素 接下来是五个队列研究，> 5000例NHLS进行了约20年。这些队列有：（i）详细 关于在类似时期以类似方式查询的常见可修改风险因素的纵向信息 时间和（ii）主动肿瘤组织收集工作。在AIM 1中，我们将进行汇总的时间依赖性分析 在预期的队列研究中，在病例对照研究中始终报道的NHL风险因素， 评估暴露时间的重要性，并计算确认的危险因素的ARP％。具体来说，我们 将评估五个主要的可修改风险因素：（i）年轻和通常的成人体重指数（BMI）； （ii） 酒精; （iii）暴露，（iv）吸烟和（v）更年期马龙治疗；和两个新兴风险因素 与免疫反应相关：（i）糖尿病和（ii）慢性感染。在AIM 2中，我们将描述 并评估肿瘤分子特征对这些病因学关联和ARP％的重要性。 具体而言，与扩散的大B细胞淋巴瘤（DLBCL）和 已经确定了表示卵泡淋巴瘤（FL）中疾病进展的独特基因突变。 在多种淋巴瘤亚型中，“双重命中”淋巴瘤的预后较差。 为福尔马林固定石蜡包裹的组织开发的新的多分析物基因表达测定现在使得 可能在流行病学研究中描述了这些独特的分子特征。因为组织 从流行病学研究中存档的仅反映了所有病例的一部分，我们将比较流行病学和 从队列研究中检索到凯撒（Kaiser）的一系列组织的组织的临床特征 南加州的永久性。这种比较将使我们能够在病例对照研究中量化生存偏差 与队列相关组织中组织确定的发现和潜在偏差。这些数量 如果确定和组织检索将使我们能够解释AIM 1风险关联，偏见将使我们能够解释目标 并相应地调整ARP％计算。