Proteomic analysis of api2-MALT1 positive gastric MALT lymphoma

描述(申请人提供)：粘膜相关淋巴组织的结外边缘区淋巴瘤是最常见的非霍奇金淋巴瘤之一，在过去20年中发病率稳步上升。最常见的受累部位是胃。在绝大多数病例中，胃结外边缘带淋巴瘤(胃MALT淋巴瘤)与幽门螺杆菌有机体感染有关。对这种疾病与幽门螺杆菌密切相关的认识，以及绝大多数肿瘤对幽门螺杆菌抗原的依赖，支持了革命性地引入抗生素方案来治疗这种形式的癌症。在这方面，在高达75%的病例中，根除抗生素会导致胃MALT淋巴瘤的消退。然而，一部分病例获得了反复的染色体易位t(11；18)，这导致了一种异常蛋白的产生，API2/MALT1融合在这种肿瘤的发病机制中起着重要的作用。重要的是，API2/MALT1阳性淋巴瘤对抗生素治疗无反应，临床病程更具侵袭性。目前，还没有已知的蛋白质组生物标志物来治疗这种耐药形式的胃MALT淋巴瘤。因此，在这一应用中，我们建议利用一套基于定量质谱学的蛋白质组学策略，并辅之以复杂的生物信息学方法来识别表达MALT淋巴瘤的API2/MALT1蛋白质组生物标记物。在特定的目标1中，我们将以一种公正的方式进行全球定量蛋白质组分析，以确定与API2/MALT1融合在成熟的人淋巴细胞中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的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检测活检标本、胃液和血浆/血清标本中API2/MALT1淋巴瘤的应用。在具体目标4中，我们将提供和传播我们的原始和串联质谱学数据，供其他团体不受限制地审问。我们的长期目标是找到可靠、敏感和特异的生物标志物，用于检测结外边缘带淋巴瘤的抗药性API2/MALT1阳性形式。这些研究对基于定量质谱学的方法识别所有形式癌症的疾病生物标记物的潜力具有广泛的影响。公共卫生相关性：受粘膜相关淋巴组织结外边缘区B细胞淋巴瘤影响最常见的部位是胃。这种形式的非霍奇金淋巴瘤与幽门螺杆菌这种细菌有机体的存在密切相关。在大多数情况下，针对机体的抗生素和抗微生物治疗是治疗这种形式的癌症的有效策略。然而，这些胃MALT淋巴瘤的一部分对抗生素治疗没有反应，并追求积极的临床过程，预后不良。这些抗生素耐药病例中的绝大多数被证明存在染色体异常，这导致了一种名为API2-MALT1的异常融合蛋白的表达。目前还没有成熟的蛋白质组生物标志物来检测这种耐药的MALT淋巴瘤。使用复杂的质谱学策略，我们将识别API2-MALT1阳性淋巴瘤的蛋白质组生物标记物。我们的研究为耐药胃MALT淋巴瘤的早期发现提供了机会。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耐药胃MALT淋巴瘤的整体战略中的关键因素。

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.