Molecular Epidemiology of AIDS-Associated Lymphoma

艾滋病相关淋巴瘤的分子流行病学

• 批准号: 6804935
• 负责人: OTONIEL MARTINEZ-MAZA
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804935
• 关键词: AIDS related neoplasm /cancer; B cell lymphoma; Burkitt's lymphoma; CD antigens; biomarker; chromosome translocation; clinical research; cytokine; enzyme linked immunosorbent assay; flow cytometry; gene rearrangement; genetic polymorphism; human tissue; immunoglobulin genes; leukocyte activation /transformation; molecular pathology; monoclonal antibody; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer immunology; polymerase chain reaction; receptor expression; serum

DESCRIPTION (Provided by the applicant): Non-Hodgkin' s B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in HIV-infected people, not only in North America and Europe, but worldwide. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-lymphoma. The proposed studies will utilize the resources of the Multicenter AIDS Cohort Study of the Natural History of AIDS (MACS). In prior studies supported by this award, elevated levels of various immune system molecules that are associated with B cell activation, including IL6 and IL10, sCD23, sCD27, sCD44, and IgE, were seen prior to the clinical detection of AIDS-lymphoma. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-lymphoma (Burkitt's/SNCCL vs. other subtypes), suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, in very recent work we saw that a single-nucleotide polymorphism (SNP) in the IL10 promoter (-592 C/C), which is known to result in increased expression of IL10, was associated with the development of AIDS-lymphoma. These findings are of great significance, since few risk factors have been identified for AIDS-lymphoma. The specific aims of the proposed studies are to determine: I ) if enhanced B cell stimulation, elevated immunoglobulin isotype switch activity, detectable c-myc:Ig gene translocations, and/or detectable circulating B cells with a germinal center-like phenotype, precede the development of AIDS- lymphoma, 2) if SNPs in the genes encoding B cell-stimulatory cytokines (IL6, IL10, TNFalpha, LTalpha, RANTES) are associated with an elevated risk for the development of AIDS-lymphoma, and 3) if subjects who have a genotype that has been seen to be associated with a decreased risk for developing AIDS-lymphoma (CCR5 delta-32 heterozygotes, SDF-1 3'UTR 801 G/G SNP, or IL10 promoter -592 A/A or A/C SNP) show lower levels of B cell activation. The accomplishment of these specific aims will add valuable new information to our understanding of the molecular epidemiology of AIDS-lymphoma, as well as the role of immune dysfunction in the generation and growth of this cancer. This information could form the foundation for future studies on the pathogenesis of AIDS-lymphoma, and may lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier and more effective clinical intervention.

描述（由申请人提供）：非霍奇金 B 细胞淋巴瘤 （艾滋病淋巴瘤）在艾滋病毒感染者中的发病率大大增加， 不仅在北美和欧洲，而且在全世界。在本提案中，研究 旨在阐明艾滋病淋巴瘤的分子流行病学。这 拟议的研究将利用多中心艾滋病队列的资源 艾滋病自然史研究（MACS）。在此支持的先前研究中 奖励，相关的各种免疫系统分子水平升高 具有 B 细胞激活作用，包括 IL6 和 IL10、sCD23、sCD27、sCD44 和 IgE， 是在临床检测出艾滋病淋巴瘤之前就已发现的。值得注意的是，有 此类 B 细胞刺激物的表达模式存在明显差异 在艾滋病淋巴瘤的不同亚型中观察到的分子（Burkitt's/SNCCL vs. 其他亚型），表明在特征上存在差异 免疫功能障碍先于这些不同亚群的发展 癌症。除此之外，在最近的工作中我们看到 IL10 启动子 (-592 C/C) 中的单核苷酸多态性 (SNP) 已知会导致 IL10 表达增加，与 艾滋病淋巴瘤的发展。这些发现具有重要意义，因为 几乎没有发现艾滋病淋巴瘤的危险因素。具体目标 拟议的研究旨在确定： I ) 是否增强 B 细胞刺激， 免疫球蛋白同种型转换活性升高，可检测到 c-myc:Ig 基因 易位，和/或可检测到的带有生发细胞的循环 B 细胞 中心样表型，先于艾滋病淋巴瘤的发展，2) 如果 SNPs 编码 B 细胞刺激性细胞因子（IL6、IL10、TNFα、LTα、 RANTES）与患以下疾病的风险升高相关 艾滋病淋巴瘤，以及 3) 如果受试者的基因型已被认为是 与降低患艾滋病淋巴瘤的风险相关（CCR5 delta-32 杂合子、SDF-1 3'UTR 801 G/G SNP 或 IL10 启动子 -592 A/A 或 A/C SNP) 显示较低水平的 B 细胞激活。这些具体工作的完成 目标将为我们对分子的理解添加有价值的新信息 艾滋病淋巴瘤的流行病学，以及免疫功能障碍在疾病中的作用 这种癌症的产生和生长。这些信息可以形成 为未来研究艾滋病淋巴瘤的发病机制奠定基础，并可能 导致能够在早期发现艾滋病淋巴瘤的新筛查技术 肿瘤发展过程，以便更早、更有效的临床 干涉。