Proteomic analysis of api2-MALT1 positive gastric MALT lymphoma

描述（由申请方提供）：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。认识到该病与H. pylori感染和绝大多数肿瘤对H.幽门螺杆菌抗原的发现支持了抗生素疗法的革命性引入，用于治疗这种形式的癌症。在这方面，抗生素根除微生物导致高达75%的胃MALT淋巴瘤消退。然而，一个子集的情况下获得一个复发性染色体易位的t（11;18），导致异常蛋白质的产生，api 2/MALT 1融合，这是重要的发病机制，这种肿瘤。重要的是，api 2/MALT 1阳性淋巴瘤对抗生素治疗无反应，其特征在于更具侵袭性的临床病程。目前，对于这种抗生素耐药形式的胃MALT淋巴瘤，还没有已知的蛋白质组学生物标志物。因此，在本申请中，我们提出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鉴定表达MALT淋巴瘤的api 2/MALT 1的蛋白质组学生物标志物。在具体目标1中，我们将以无偏的方式进行全局定量蛋白质组学分析，以鉴定与成熟人淋巴细胞中api 2/MALT 1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api 2/MALT 1阳性淋巴瘤。在具体目标3中，我们将研究api 2/MALT 1特异性生物标志物用于检测活检标本、胃液和血浆/血清样品中的api 2/MALT 1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，供其他团体进行不受限制的询问。我们的长期目标是确定稳健，敏感和特异的生物标志物，用于检测结边缘区淋巴瘤的耐药api 2/MALT 1阳性形式。这些研究对基于定量质谱的方法用于鉴定所有形式癌症的疾病生物标志物的潜力具有广泛的意义。

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.