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

基本信息

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
项目类别：
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&apos s Lymphoma Nurses&apos 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&apos s lymphoma modifiable risk molecular subtypes outcome forecast prospective protein expression teacher tumor young adult

项目摘要

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，我们的目标是直接解决 NHL 病因学知识中的关键差距，并促进未来研究的“最佳实践”主要是由病例对照汇总推动的。研究提出了许多可改变的风险因素，但 (i) 也可能受到以下因素的影响未测量的偏差（生存率、召回率）；(ii) 无法计算群体归因风险 (ARp%)；以及（iii）由于缺乏可用于描述分子亚型的肿瘤组织而受到限制。目标是通过对超过 500,000 人的汇总分析来评估所谓的 NHL 风险因素对超过 5000 例 NHL 事件的五项队列研究进行了约 20 年的跟踪研究，这些队列具有：(i) 详细信息。在相似时期内以相似方式查询的常见可改变风险因素的纵向信息时间，以及 (ii) 积极的肿瘤组织收集工作在目标 1 中，我们将进行汇总的时间依赖性分析。在前瞻性队列研究中评估病例对照研究中一致报告的 NHL 危险因素，具体来说，我们评估暴露时间的重要性，并计算已确认风险因素的 ARp%。将评估五个关键的据称可改变的风险因素：（i）年轻人和普通成年人的体重指数（BMI）；（ii）酒精；(iii) 阳光照射；(iv) 吸烟；(v) 更年期激素治疗；以及两个新出现的危险因素；与免疫反应相关的：(i) 糖尿病和 (ii) 慢性感染在目标 2 中，我们将描述其特征。并评估肿瘤分子特征对这些病因关联和 ARp% 的重要性。具体而言，独特的基因表达模式与弥漫性大 B 细胞淋巴瘤 (DLBCL) 和已经确定了表明滤泡性淋巴瘤（FL）疾病进展的不同基因突变。 “双重打击”淋巴瘤在多种淋巴瘤亚型中也被证明预后不良。为福尔马林固定石蜡包埋的组织测定开发的新的多分析物基因表达现在使得在流行病学研究中描述这些独特的分子特征是可能的，因为组织。流行病学研究存档仅反映所有病例的一部分，我们将比较流行病学和从队列研究中检索到的组织的临床特征与 Kaiser 的一系列无偏见组织这种比较将使我们能够量化病例对照研究中的生存偏差。队列相关组织中组织确定的发现和潜在偏差这些量化。病例确定和组织检索中的偏差将使我们能够解释由此产生的目标 1 风险关联并相应调整 ARp% 计算。