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。很少有生物标记物可用于非霍奇金淋巴瘤 (NHL) 的早期检测或进展，非霍奇金淋巴瘤 (NHL) 是一种免疫细胞癌症，它经历了最大且仍无法解释的癌症之一 - 发病率增加，每年诊断出超过 66,000 例新病例。 NHL 研究中识别早期检测和预后生物标志物的两个有前景的领域是 (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对参加洛杉矶 (LA) 县 NHL 病例对照研究的 1000 多名诊断为 NHL 的女性（2004-2008 年）的 NHL 生存的作用。目前，联盟的努力明确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 与 NHL 生存之间存在关联。在探索性分析中，我们进一步确定了 HLA-DRB1*13 和 HLA-Bw4 与 NHL 生存的关联，HLA 等位基因与已确定的 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。我们相信，有必要对免疫基因的作用进行详细研究，特别关注 HLA 在 NHL 生存中的作用，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 (HLA) 以及与 HLA 相关的其他关键先验基因（包括 TNF）的遗传变异对总体生存的预后意义。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 疾病过程本身。一系列基于基因表达数据的里程碑式出版物已经产生了分子定义的 NHL 亚型，反映了不同的生存情况。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，但复制基于 IHC 的算法的尝试却很复杂。因此，我们提出对这些算法进行系统评估，以推动这项转化研究向前发展。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期的预后意义，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。我们的研究是免疫疗法（利妥昔单抗）时代（2000 年后）治疗 NHL 病例的少数研究之一，使结果可推广到当前的患者群体。我们成功检索肿瘤组织的能力 获得详细的治疗信息将有助于宿主遗传学和分子肿瘤标志物对 NHL 生存的预测。公共卫生相关性：这项研究的成功完成将有助于了解 NHL 生存中的宿主遗传变异和肿瘤标志物。 公共卫生相关性：很少有生物标记物可用于非霍奇金淋巴瘤 (NHL) 的早期检测或进展，非霍奇金淋巴瘤 (NHL) 是一种免疫细胞癌症，其发病率增长幅度最大（但仍无法解释），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 研究的两个有前景的领域，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 生存的补充假设。

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.