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，直接推进预防研究。非霍奇金淋巴瘤（NHL）是一种免疫细胞癌，其发病率增加最多，至今仍无法解释，每年有超过66,000例新病例被诊断出来，目前很少有生物标志物可用于早期检测或进展。NHL研究的两个有前途的领域是确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。我们的研究目的是评估宿主遗传变异和肿瘤分子亚型在洛杉矶（LA）县NHL病例对照研究中超过1000名被诊断为NHL的女性（2004-2008）的NHL生存中的作用。目前，联合研究明确了人类白细胞抗原（HLA） I类和II类基因和肿瘤坏死因子（TNF）基因在NHL病因学中的作用。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- drb1 *13和HLA- bw4与NHL生存的关系，HLA等位基因与NHL危险因素（如病毒感染、获得性免疫缺陷综合征）显著相关。我们相信详细研究免疫基因的作用，特别是HLA在NHL生存中的作用是有必要的，以跟踪这些有趣的结果。在Aim 1中，我们将研究人类白细胞抗原（HLA）遗传变异和其他与HLA相关的关键先天基因（包括TNF）在总生存率中的预后意义。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进展

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.