Molecular epidemiology of non-Hodgkin lymphoma prognosis and prevention

非霍奇金淋巴瘤预后和预防的分子流行病学

• 批准号: 8272486
• 负责人: Sophia S Wang
• 金额: $ 71.64万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-17 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272486
• 关键词: 6p21.3; Acquired Immunodeficiency Syndrome; Address; Affect; Algorithms; Alleles; Archives; Area; Behavior; Biological Assay; Biological Markers; Case-Control Studies; Categories; Cells; Characteristics; Clinical; Clinical Research; County; Data; Diagnosis; Disease; Disease Outcome; Disease Progression; Early Diagnosis; Enrollment; Etiology; Evaluation; Event; Female; Follicular Lymphoma; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Goals; HLA Antigens; Haplotypes; Immune; Immune response; Immunogenetics; Immunotherapy; Incidence; Infection; Inflammatory; Inflammatory Response; International; Investigation; Link; Los Angeles; MHC Class II Genes; Major Histocompatibility Complex; Malignant Neoplasms; Medical Surveillance; Molecular; Molecular Epidemiology; Molecular Genetics; National Cancer Institute; Nature; Non-Hodgkin' s Lymphoma; Outcome; Pathology; Population; Prevention; Prevention Research; Process; Prognostic Factor; Publications; Reaction; Research; Risk; Risk Factors; Role; Series; Simulate; Specimen; Staining method; Stains; Structure of germinal center of lymph node; TNF gene; Testing; Translational Research; Tumor Markers; Tumor Necrosis Factor-alpha; Tumor Subtype; Tumor Tissue; Virus Diseases; base; cancer initiation; cytokine; experience; follow-up; genetic linkage; improved; indexing; large cell Diffuse non-Hodgkin' s lymphoma; outcome forecast; patient population; population based; prognostic; public health relevance; response; rituximab; tumor

DESCRIPTION (provided by applicant): Biomarker-based early detection can directly advance prevention research by identifying key molecular events that drive cancer initiation, progression, and outcomes. Few biomarkers exist for the early detection or progression of non-Hodgkin lymphoma (NHL), a cancer of immune cells which has experienced one of the largest and still unexplained - increases in incidence and for which more than 66,000 new cases are diagnosed annually. Two promising areas of NHL research for identifying biomarkers of early detection and prognosis are (i.) host genetics and (ii) molecularly-defined tumor subtypes. Our study objective is to evaluate the role of host genetic variations and tumor molecular subtypes in NHL survival among over 1000 females diagnosed with NHL (2004-2008) who were enrolled in the Los Angeles (LA) County NHL Case-Control study. Consortial efforts now clearly implicate human leukocyte antigen (HLA) Class I and Class II genes and the tumor necrosis factor (TNF) gene in NHL etiology. Clinical studies further suggest associations between HLA and TNF in NHL survival. In exploratory analyses, we have further identified associations with NHL survival with HLA-DRB1*13 and HLA-Bw4, HLA alleles notably associated with established NHL risk factors (e.g., viral infections, acquired immunodeficiency syndrome). We believe detailed investigation into the role of immune genes with a particular focus on HLA in NHL survival is warranted to follow-up these intriguing results. In Aim 1 we will investigate the prognostic significance of genetic variation in the human leukocyte antigen (HLA), and other key a priori genes linked to HLA, including TNF, in overall survival. While host genetics may reflect a general immune milieu that affects disease progression, molecular characteristics within the tumor are thought to reflect the disease process itself. A series of landmark publications based on gene expression data has yielded molecularly defined NHL subtypes that reflect different survival. A number of tumor marker algorithms based on immunohistochemical (IHC) staining have been developed to simulate these molecular subtypes but attempts to replicate IHC-based algorithms have been mixed. We thus propose a systematic evaluation of these algorithms to move this translational research forward. In Aim 2, we will evaluate the prognostic significance of a priori and emerging tumor markers in overall survival, with a focus on the two most common NHL subtypes, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Our study is among only a handful with NHL cases treated in the immunotherapy (rituximab) era (post-2000), making results generalizable to current patient populations. Our ability to successfully retrieve tumor tissue and obtain detailed therapy information will inform the predictive nature of host genetics and molecular tumor markers in NHL survival. Public health relevance: successful completion of this study will contribute to the understanding of host genetic variation and tumor markers in NHL survival. PUBLIC HEALTH RELEVANCE: Few biomarkers exist for the early detection or progression of non-Hodgkin lymphoma (NHL), a cancer of immune cells, which has experienced one of the largest - and still unexplained - increases in incidence and for which more than 66,000 new cases are diagnosed annually. Among NHL cases enrolled in the Los Angeles County NHL Case-Control Study, we will examine two promising areas of NHL research for identifying biomarkers of prognosis. Specifically, we will test the complementary hypotheses that host genetics (to reflect the immune milieu) and tumor molecular subtypes (to reflect the disease process) can predict NHL survival.

描述(由申请人提供)：基于生物标记物的早期检测可以通过识别驱动癌症发生、进展和结果的关键分子事件，直接推动预防研究。目前几乎没有用于早期发现或进展的非霍奇金淋巴瘤(NHL)的生物标志物，这是一种免疫细胞癌，发病率经历了最大但仍无法解释的增长之一，每年诊断出超过66,000例新病例。非霍奇金淋巴瘤研究的两个有前景的领域是：(1)宿主遗传学和(Ii)分子定义的肿瘤亚型。我们的研究目标是评估宿主遗传变异和肿瘤分子亚型在超过1000名确诊为NHL的女性(2004-2008年)中的作用，这些女性参加了洛杉矶(LA)县NHL病例对照研究。联合研究表明人类白细胞抗原(HLAI)和HLAII类基因以及肿瘤坏死因子(TNF)基因在NHL的病因中有明显的关联。临床研究进一步提示，人类白细胞抗原和肿瘤坏死因子与非霍奇金淋巴瘤的存活率有关。在探索性分析中，我们进一步确定了与非霍奇金淋巴瘤存活率相关的基因与人类白细胞抗原-DRB1*13和人类白细胞抗原-Bw4，以及与已建立的非霍奇金淋巴瘤危险因素(如病毒感染、获得性免疫缺陷综合征)显著相关的等位基因。我们认为，有必要对免疫基因在NHL生存中的作用进行详细的研究，特别是对人类白细胞抗原的研究，以跟进这些有趣的结果。在目标1中，我们将研究人类白细胞抗原(人类白细胞抗原)以及其他与人类白细胞抗原相关的关键先验基因(包括肿瘤坏死因子)的遗传变异在总体生存中的预后意义。虽然宿主遗传学可能反映了影响疾病进展的一般免疫环境，但肿瘤内的分子特征被认为反映了 疾病本身就是一个过程。基于基因表达数据的一系列里程碑式的出版物已经产生了反映不同存活率的分子定义的NHL亚型。许多基于免疫组织化学(IHC)染色的肿瘤标记物算法已经被开发出来模拟这些分子亚型，但复制基于IHC的算法的尝试是混合的。因此，我们建议对这些算法进行系统的评估，以推动这一翻译研究的发展。在目标2中，我们将评估先验和新出现的肿瘤标志物对总生存率的预后意义，重点放在两个最常见的NHL亚型，弥漫性大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤。我们的研究是在免疫疗法时代(2000年后)治疗的少数NHL病例之一，使结果可以推广到当前的患者群体。我们成功地取回肿瘤组织和 获得详细的治疗信息将为宿主遗传学和分子肿瘤标志物对NHL生存的预测性质提供信息。公共卫生相关性：这项研究的成功完成将有助于了解宿主遗传变异和肿瘤标记物在NHL生存中的作用。 与公共卫生相关：非霍奇金淋巴瘤(NHL)是一种免疫细胞癌症，发病率增长幅度最大，但仍无法解释，每年新诊断病例超过66,000例，目前几乎没有生物标志物可用于早期发现或进展。在参加洛杉矶县NHL病例对照研究的NHL病例中，我们将检查NHL研究的两个有前途的领域，以确定预后的生物标志物。具体地说，我们将测试宿主遗传学(反映免疫环境)和肿瘤分子亚型(反映疾病过程)可以预测NHL生存的互补性假设。