Novel Biomarkers of Asbestos Carcinogenesis

说明(由申请人提供)：NIOSH认识到有必要研究开发测量工作场所暴露对健康不利影响的早期标记的方法。这对石棉相关癌症尤其重要，因为在国家职业研究议程的行业计划中，石棉仍然是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跨行业计划关注的主要疾病类别；从全球范围来看，估计每年有超过10万名工人死于与石棉相关的疾病，特别是癌症。在对一组石棉肺病例的有限数量的银行血清样本进行蛋白质组学分析的初步研究中，我们初步确定了新的Kinesin家族蛋白生物标记物(KIF5A和KIF18A)，它们可能与这些工人随后的癌症发展高度相关。这项建议的目的是通过使用酶联免疫吸附分析(ELISA)来系统和定量地跟踪这一发现，以分析该队列中所有110名工人的364份血清样本中KIF5A和KIF18A的水平。这些水平将与这些工人随后的癌症发展相关。此外，还可以从一些由此产生的肿瘤中获得肿瘤组织样本，并将通过免疫组织化学对KIF5A和KIF18A的表达水平进行定量分析，这些生物标志物的血清水平将与肿瘤中的表达水平相关。这项研究将是对动蛋白作为潜在的癌症血清生物标记物的第一次系统研究，如果成功，将证明这些动蛋白生物标记物可能有助于识别石棉肺患者，这些人患癌症的风险最高，然后可以选择他们进行更积极和有针对性的预防/治疗干预，从而减轻与石棉相关的恶性肿瘤的负担。 公共卫生相关性：这项研究具有重大的公共卫生相关性，因为美国有数十万工人接触过石棉，并面临与石棉相关的恶性肿瘤的风险。这项研究的目标是开发潜在的新生物标记物，用于预测这些工人的癌症风险。然后，这些生物标志物可以用来识别那些接触石棉的工人的癌症风险最高，这样他们就可以成为预防或早期治疗的目标，以减少因接触石棉而导致的癌症死亡和残疾的负担。

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.