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: 8631073
• 负责人: Sophia S Wang
• 金额: $ 62.09万
• 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/8631073
• 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; 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.

描述（由申请人提供）：基于生物标志物的早期检测可以通过识别促进癌症开始，进展和结果的关键分子事件来直接推动预防研究。很少有生物标志物可用于早期检测或进展非霍奇金淋巴瘤（NHL），这是一种免疫细胞的癌症，它经历了最大且仍无法解释的一种 - 发病率增加，每年被诊断出66,000多例新病例。 NHL研究的两个有希望的领域，用于鉴定早期检测和预后的生物标志物（i。）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NHL存活中的作用，其中1000多名被诊断为NHL（2004-2008）的女性，这些女性在洛杉矶（LA）NHL县NHL病例对照研究中的作用。现在，联盟的工作清楚地暗示了人类白细胞抗原（HLA）I类和II类基因以及NHL病因中的肿瘤坏死因子（TNF）基因。临床研究进一步表明NHL存活中HLA和TNF之间的关联。在探索性分析中，我们进一步鉴定了与HLA-DRB1*13和HLA-BW4，HLA等位基因的NHL存活相关的关联，它与已建立的NHL危险因素（例如病毒感染，获得性免疫缺陷综合征）显着相关。我们认为，有必要详细研究免疫基因在NHL生存中的特定关注的作用，以跟进这些有趣的结果。在AIM 1中，我们将研究人类白细胞抗原（HLA）遗传变异的预后意义，以及其他与HLA有关的先验基因，包括TNF，包括TNF，在整体生存中。尽管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 疾病过程本身。基于基因表达数据的一系列具有里程碑意义的出版物产生了反映不同生存率的分子定义的NHL亚型。已经开发了许多基于免疫组织化学（IHC）染色的肿瘤标记算法来模拟这些分子亚型，但尝试复制基于IHC的算法的尝试混合在一起。因此，我们提出了对这些算法的系统评估，以推动这一转化研究的前进。在AIM 2中，我们将评估先验和新兴肿瘤标记物在整体生存中的预后意义，重点是两种最常见的NHL亚型，弥漫性大B细胞淋巴瘤（DLBCL）和卵泡淋巴瘤。我们的研究仅是在免疫疗法（Rituximab）时代（2000年后）治疗的NHL病例的少数人之一，这使得可推广到当前患者人群的结果。我们成功检索肿瘤组织的能力和 获得详细的治疗信息将为NHL存活中宿主遗传学和分子肿瘤标记的预测性提供信息。