Proteomic analysis of api2-MALT1 positive gastric MALT lymphoma

描述（由申请人提供）：结外边缘区粘膜相关淋巴组织淋巴瘤是最常见的非霍奇金淋巴瘤之一，在过去的二十年中发病率稳步上升。最常见的受累部位是胃。胃结外边缘区淋巴瘤（胃MALT淋巴瘤）在绝大多数病例中与幽门螺杆菌感染有关。认识到这种疾病与幽门螺杆菌的密切联系以及绝大多数肿瘤对幽门螺杆菌抗原的依赖性，支持了革命性地引入抗生素治疗这种癌症的方案。在这方面，抗生素根除生物体可导致高达75%的胃MALT淋巴瘤消退。然而，一小部分病例获得复发性t染色体易位（11;18），导致异常蛋白api2/MALT1融合的产生，这在该肿瘤的发病机制中很重要。重要的是，api2/ malt1阳性淋巴瘤对抗生素治疗无反应，其特点是更具侵袭性的临床过程。目前，还没有已知的蛋白质组学生物标志物用于这种抗生素耐药形式的胃MALT淋巴瘤。因此，在本应用中，我们建议利用一套基于定量质谱的蛋白质组学策略，由复杂的生物信息学方法支持，以鉴定表达MALT淋巴瘤的api2/MALT1的蛋白质组学生物标志物。在具体目标1中，我们将以公正的方式进行全球定量蛋白质组学分析，以确定成熟人类淋巴样细胞中与api2/MALT1融合表达相关的蛋白质组学变化。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，我们将提供和传播我们的原始和串联质谱数据供其他组织无限制地讯问。我们的长期目标是确定稳健、敏感和特异性的生物标志物，用于检测耐药api2/ malt1阳性结外边缘区淋巴瘤。这些研究对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具有广泛的意义。公共卫生相关性：结外边缘区粘膜相关淋巴组织b细胞淋巴瘤最常见的发病部位是胃。这种形式的非霍奇金淋巴瘤与一种细菌有机体幽门螺杆菌的存在密切相关。在大多数情况下，针对生物体的抗生素和抗菌治疗是治疗这种癌症的有效策略。然而，这些胃MALT淋巴瘤的一个亚群对抗生素治疗没有反应，并追求积极的临床过程，预后不良。绝大多数这些抗生素耐药病例已被证明具有染色体畸变，导致异常融合蛋白api2-MALT1的表达。目前还没有成熟的蛋白质组学生物标志物来检测这种抗生素耐药形式的MALT淋巴瘤。使用复杂的质谱分析策略，我们将确定api2- malt1阳性淋巴瘤的蛋白质组学生物标志物。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耐药胃MALT淋巴瘤的整体策略的关键因素。

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.