Proteomic analysis of api2-MALT1 positive gastric MALT lymphoma

api2-MALT1阳性胃MALT淋巴瘤的蛋白质组学分析

• 批准号: 8035900
• 负责人: KOJO S. J. ELENITOBA-JOHNSON
• 金额: $ 27.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-26 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035900
• 关键词: Affect; Aggressive Clinical Course; Anatomic Sites; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigens; Behavior Therapy; Bioinformatics; Biological Markers; Biopsy Specimen; Cells; Characteristics; Chimeric Proteins; Chromosomal translocation; Chromosome abnormality; Communities; Data; Dependence; Detection; Diagnosis; Diagnostic; Disease; Disease Association; Early Diagnosis; Event; Extranodal; Gastric Juice; Gastric lymphoma; Gastric mucosa; Generations; Goals; Health; Helicobacter Infections; Helicobacter pylori; Human; Immunohistochemistry; Incidence; Indium; Infection; Interest Group; Ions; Isotopes; Knowledge; Light; Lymphoid Cell; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mass Spectrum Analysis; Molecular Profiling; Monitor; NIH Program Announcements; Neoplasms; Non-Hodgkin' s Lymphoma; Oncogenic; Organism; Pathogenesis; Pathway interactions; Patients; Peptides; Plasma; Proteins; Proteomics; Reaction; Recurrence; Resistance; Risk; Sampling; Series; Site; Stomach; Therapeutic; Treatment Protocols; Trypsin; Validation; Western Blotting; antimicrobial; base; computerized tools; human tissue; minimally invasive; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; outcome forecast; response; t(11; 18)(q21; q21); tandem mass spectrometry; therapeutic target; treatment strategy; tumor

DESCRIPTION (provided by applicant): Extranodal marginal zone lymphomas of mucosa associated lymphoid tissue are one of the most common forms of non-Hodgkin lymphoma with steadily increasing incidence over the last two decades. The most common site of involvement is the stomach. Extranodal marginal zone lymphomas of the stomach (gastric MALT lymphomas) are associated with infection by the Helicobacter pylori organism in the vast majority of cases. The recognition of strong association of this disease with H. pylori and the dependence of the vast majority of the tumors on H. pylori antigen supported the revolutionary introduction of antibiotic regimens for the treatment of this form of cancer. In this regard, antibiotic eradication of the organism leads to regression of the gastric MALT lymphomas in up to 75% of cases. However, a subset of cases acquire a recurrent chromosomal translocation the t(11;18) which leads to the generation of an abnormal protein, the api2/MALT1 fusion that is important in the pathogenesis of this neoplasm. Importantly, api2/MALT1-positive lymphomas are unresponsive to antibiotic therapy and are characterized by a more aggressive clinical course. Currently, there are no known proteomic biomarkers for this antibiotic resistant form of gastric MALT lymphoma. Accordingly, in this application, we propose to utilize a suite of quantitative mass spectrometry-based proteomics strategies supported by sophisticated bioinformatics approaches to identify proteomic biomarkers of api2/MALT1 expressing MALT lymphomas. In specific aim 1, we will perform global quantitative proteomic analysis in an unbiased fashion to identify the proteomic changes associated with expression of the api2/MALT1 fusion in mature human lymphoid cells. In specific aim 2, we will develop a series of highly selective ion reaction monitoring strategies to detect api2/MALT1-positive lymphomas. In specific aim 3, we will investigate the utility of the api2/MALT1 specific biomarkers for the detection of api2/MALT1 lymphomas in biopsy specimens, gastric juice and in plasma/serum samples. In specific aim 4, we will make accessible and disseminate our raw and tandem mass spectrometry data for unrestricted interrogation by other groups. Our long-term goal is to identify robust, sensitive and specific biomarkers for the detection of the antibiotic-resistant api2/MALT1-positive form of extranodal marginal zone lymphoma. These studies have broad implications for the potential of quantitative mass spectrometry-based approaches for the identification of disease biomarkers for all forms of cancer. PUBLIC HEALTH RELEVANCE: The most common site affected by extranodal marginal zone B-cell lymphomas of mucosa associated lymphoid tissue is the stomach. This form of non-Hodgkin lymphoma is strongly and causally associated with the presence of a bacterial organism, Helicobacter pylori. In the majority of cases, antibiotic and antimicrobial therapy targeting the organism is an effective strategy for the treatment of this form of cancer. However, a subset of these gastric MALT lymphomas does not respond to antibiotic therapy and pursue an aggressive clinical course with adverse prognosis. The vast majority of these antibiotic resistant cases have been shown to harbor a chromosomal aberration which leads to the expression of an abnormal fusion protein known as api2-MALT1. There are no well-developed proteomic biomarkers for detection of this antibiotic resistant form of MALT lymphoma. Using sophisticated mass spectrometry strategies, we will identify the proteomic biomarkers of api2-MALT1-positive lymphomas. Our studies offer an opportunity for the early detection of antibiotic resistant gastric MALT lymphoma. The ability to routinely detect api2-MALT1-positive lymphoma with a minimally invasive approaches is a critical element in the overall strategy for the effective management and therapeutic monitoring of antibiotic resistant gastric MALT lymphoma.

描述（由申请人提供）：粘膜相关淋巴组织的结外边缘区淋巴瘤是非霍奇金淋巴瘤最常见的形式之一，在过去二十年中发病率稳步增加。最常见的受累部位是胃。绝大多数病例中，胃结外边缘区淋巴瘤（胃 MALT 淋巴瘤）与幽门螺杆菌感染有关。认识到这种疾病与幽门螺杆菌密切相关以及绝大多数肿瘤对幽门螺杆菌抗原的依赖性支持革命性地引入抗生素疗法来治疗这种形式的癌症。在这方面，抗生素根除微生物可使高达 75% 的胃 MALT 淋巴瘤消退。然而，一部分病例会发生反复染色体易位 t(11;18)，从而导致异常蛋白（api2/MALT1 融合蛋白）的产生，该蛋白在这种肿瘤的发病机制中发挥着重要作用。重要的是，api2/MALT1 阳性淋巴瘤对抗生素治疗无反应，并且具有更具侵袭性的临床病程。目前，这种抗生素耐药性胃 MALT 淋巴瘤尚无已知的蛋白质组生物标志物。因此，在本申请中，我们建议利用一套由复杂的生物信息学方法支持的基于定量质谱的蛋白质组学策略来识别表达 api2/MALT1 的 MALT 淋巴瘤的蛋白质组生物标志物。在具体目标 1 中，我们将以公正的方式进行全局定量蛋白质组分析，以确定与成熟人淋巴细胞中 api2/MALT1 融合表达相关的蛋白质组变化。在具体目标2中，我们将开发一系列高选择性离子反应监测策略来检测api2/MALT1阳性淋巴瘤。在具体目标 3 中，我们将研究 api2/MALT1 特异性生物标志物在活检标本、胃液和血浆/血清样本中检测 api2/MALT1 淋巴瘤的效用。在具体目标 4 中，我们将提供并传播我们的原始和串联质谱数据，以便其他团体不受限制地询问。我们的长期目标是确定稳健、敏感和特异的生物标志物，用于检测抗生素耐药的 api2/MALT1 阳性结外边缘区淋巴瘤。这些研究对于基于定量质谱的方法识别所有形式癌症的疾病生物标志物的潜力具有广泛的影响。 公众健康相关性：最常见受粘膜相关淋巴组织结外边缘区 B 细胞淋巴瘤影响的部位是胃。这种形式的非霍奇金淋巴瘤与细菌有机体幽门螺杆菌的存在密切相关。在大多数情况下，针对微生物的抗生素和抗菌疗法是治疗这种癌症的有效策略。然而，这些胃 MALT 淋巴瘤中的一部分对抗生素治疗没有反应，并且会出现侵袭性临床病程，预后不良。绝大多数这些抗生素耐药病例已被证明存在染色体畸变，导致一种称为 api2-MALT1 的异常融合蛋白的表达。目前尚无成熟的蛋白质组生物标志物可用于检测这种抗生素耐药形式的 MALT 淋巴瘤。使用复杂的质谱策略，我们将鉴定 api2-MALT1 阳性淋巴瘤的蛋白质组生物标志物。我们的研究为早期检测抗生素耐药性胃 MALT 淋巴瘤提供了机会。通过微创方法常规检测 api2-MALT1 阳性淋巴瘤的能力是有效管理和治疗监测抗生素耐药性胃 MALT 淋巴瘤总体策略的关键要素。