Molecular epidemiology of non-Hodgkin lymphoma prognosis and prevention

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驱动癌症发生、进展和结果的关键分子事件来直接推进预防研究。对于非霍奇金淋巴瘤（NHL）的早期检测或进展，几乎没有生物标志物存在，这是一种免疫细胞癌症，经历了最大的和仍然无法解释的发病率增加之一，每年诊断出超过66，000例新病例。NHL研究的两个有前途的领域，用于确定早期检测和预后的生物标志物是（i.）宿主遗传学和（ii）分子定义的肿瘤亚型。我们的研究目的是评估宿主遗传变异和肿瘤分子亚型在超过1000名女性NHL患者（2004-2008年）中的作用，这些女性被诊断为NHL，并参加了洛杉矶（LA）县NHL病例对照研究。联合研究表明，人类白细胞抗原（HLA）I类和II类基因以及肿瘤坏死因子（TNF）基因与NHL病因有关。临床研究进一步表明HLA和TNF在NHL生存中的相关性。在探索性分析中，我们进一步确定了HLA-DRB 1 *13和HLA-Bw 4与NHL生存的相关性，HLA等位基因与已确定的NHL风险因素显著相关（例如，病毒感染、获得性免疫缺陷综合征）。我们相信，对免疫基因的作用，特别是对HLA在NHL生存中的作用进行详细的调查是必要的，以跟踪这些有趣的结果。在目的1中，我们将研究人类白细胞抗原（HLA）和其他与HLA相关的关键先验基因（包括TNF）的遗传变异在总生存期中的预后意义。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的进展。 疾病本身。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生存期的分子定义的NHL亚型。已经开发了许多基于免疫组织化学（IHC）染色的肿瘤标志物算法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，我们提出了一个系统的评估这些算法，推动这一转化的研究。在目标2中，我们将评估先验和新出现的肿瘤标志物在总生存期中的预后意义，重点关注两种最常见的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治疗（利妥昔单抗）时代（2000年后）治疗的少数NHL病例之一，使结果可推广到当前的患者人群。我们成功取出肿瘤组织的能力 获得详细的治疗信息将告知宿主遗传学和分子肿瘤标志物在NHL生存中的预测性质。公共卫生相关性：本研究的成功完成将有助于理解宿主遗传变异和肿瘤标志物在NHL生存中的作用。 公共卫生相关性：对于非霍奇金淋巴瘤（NHL）的早期检测或进展，几乎没有生物标志物存在，这是一种免疫细胞癌症，经历了最大的-仍然无法解释的-发病率增加之一，每年诊断出超过66，000例新病例。在参加洛杉矶县NHL病例对照研究的NHL病例中，我们将研究NHL研究的两个有前途的领域，以确定预后的生物标志物。具体来说，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生存的互补假设。

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.