Novel Biomarkers of Asbestos Carcinogenesis

描述（由申请人提供）：NIOSH认识到需要进行研究，以制定测量工作场所暴露对健康不利影响的早期标志的方法。这对于石棉相关的癌症尤其重要，因为石棉仍然是国家职业研究议程部门计划所针对的几个行业的主要职业健康风险，如建筑、制造、采矿、运输和公用事业，癌症仍然是NIOSH跨部门计划关注的主要疾病类别；据估计，全世界每年有10多万工人死于与石棉有关的疾病，特别是癌症。在基于有限数量的石棉沉滞病例队列血清样本的蛋白质组学分析的初步研究中，我们初步确定了新的动力蛋白家族蛋白生物标志物（KIF5A和KIF18A），它们可能与这些工人随后的癌症发展高度相关。本提案的目的是通过使用酶联免疫吸附法（elisa）以系统和定量的方式跟踪这一发现，分析该队列中所有110名工人的364份血清样本中的KIF5A和KIF18A水平。这些水平将与这些工人随后的癌症发展相关。此外，从一些最终的肿瘤中获得肿瘤组织样本，将通过免疫组织化学定量分析KIF5A和KIF18A的表达水平，这些生物标志物的血清水平将与肿瘤中的表达水平相关。这项研究将是第一个将动力蛋白作为潜在的癌症血清生物标志物的系统研究，如果成功，将证明这些动力蛋白生物标志物可以用于识别那些患癌症风险最高的石棉沉滞症患者，然后可以选择更积极和有针对性的预防/治疗干预措施，从而减少石棉相关恶性肿瘤的负担。

DESCRIPTION (provided by applicant): NIOSH recognizes the need for research for the development of methods for measuring the early markers of adverse health effects from workplace exposures. This is especially important for asbestos-related cancers because asbestos remains a major occupational health risk in several of the industries targeted in the National Occupational Research Agenda's Sectors Program, such as construction, manufacturing, mining, and transportation and utilities, and cancer remains a major disease category of concern in the NIOSH Cross- Sector Program; world-wide, it is estimated that more than a hundred thousand workers die each year from asbestos-related diseases, particularly cancer. In preliminary studies based on the proteomic analysis of a limited number of banked serum samples from a cohort of asbestosis cases, we have tentatively identified novel kinesin family protein biomarkers (KIF5A and KIF18A) that may be highly correlated with the subsequent development of cancer in these workers. The purpose of this proposal is to follow up on this finding in a systematic and quantitative fashion by using enzyme-linked immunosorbent assays (ELISAs) to analyze all of the 364 serum samples from all of the 110 workers in this cohort for levels of KIF5A and KIF18A. These levels will be correlated with the subsequent development of cancer in these workers. In addition, tumor tissue samples are available from some of the resultant tumors which will be quantitatively analyzed by immunohistochemistry for the levels of expression of KIF5A and KIF18A, and the serum levels of these biomarkers will be correlated with the levels of expression in the tumors. This research would be the first systematic study of kinesin proteins as potential serum biomarkers for cancer, and, if successful, would demonstrate that these kinesin biomarkers could be useful for identifying those individuals with asbestosis who are at the highest risk for developing cancer and who could then be selected for more aggressive and targeted preventive/therapeutic interventions, thus reducing the burden of asbestos-related malignancies. PUBLIC HEALTH RELEVANCE: This research has significant Public Health Relevance because hundreds of thousands of workers in the U.S. have been exposed to asbestos and are at risk for asbestos-related malignancies. The goal of this research is to develop potential new biomarkers for cancer risk in these workers. These biomarkers could then be used to identify those asbestos-exposed workers at the highest risk for cancer so that they could be targeted with interventions for prevention or early treatment to reduce the burden of cancer deaths and disability from asbestos exposures.