The Epidemiology of Molecular Alterations in Mesothelioma

描述(由申请人提供)：长期接触石棉与胸膜间皮瘤有关。然而，石棉在诱发间皮瘤中的作用模式仍未完全描述，对于肿瘤抑制基因的表观遗传失活与致癌暴露之间的关联知之甚少。石棉不是一种直接作用的诱变剂，但具有致癌作用；因此，众所周知，它也会在接触过石棉的人的肺部持续存在。我们的初步数据表明，石棉纤维负荷与表观遗传沉默和DNA甲基化失活的肿瘤抑制基因的数量显著相关。我们建议利用布里格姆妇女医院(BWH)新开发的国际间皮瘤计划(IMP)来扩大这项研究，在那里，新的手术治疗方案首次使对间皮瘤患者的肿瘤组织进行研究成为可能。我们建议测试假设，即肿瘤抑制基因的表观遗传失活，通过评估DNA甲基化情况，与石棉纤维类型和负担有关。此外，我们将使用一种新的伪迹抵抗方法来检验SV40病毒参与间皮瘤的假设，并研究miRNAs在间皮瘤中的作用，询问这是否可能是这种疾病的新的生物标记物。最后，我们将检验间皮瘤的存活率与肿瘤的个体分子特征有关的假设。我们的数据还将与BWH作为IMP的一部分生成的表达谱数据汇集在一起，产生非常丰富的全球基因组数据存储库，用于恶性间皮瘤系统生物学的探索性分析。总而言之，我们建议继续招募和研究转诊到BWH的患者，以进行这种通常是致命的癌症的新手术治疗。我们将研究他们肿瘤的分子特征，提出肿瘤中病变的特征与他们接触石棉的性质以及他们对治疗的反应有关。间皮瘤是一种最常见的致命癌症，由石棉暴露引起。我们建议研究石棉在体内作用的新机制(包括通过诱导染色体构象改变而使基因失活和沉默)，将这些与石棉暴露的定量措施联系起来。例如，这可能有助于解释为什么即使是小剂量的石棉暴露也会造成致命的癌症风险。

DESCRIPTION (provided by applicant): Exposure to asbestos has long been associated with pleural mesothelioma. The mode of action of asbestos in inducing mesothelioma, however, remains to be completely described, and relatively little is known about the association of epigenetic inactivation of tumor suppressor genes with carcinogenic exposures. Asbestos is not a direct-acting mutagen, but is carcinogenic; as such, it is also known to persist in the lungs of exposed individuals. Our preliminary data has demonstrated that asbestos fiber burden is significantly associated with the number of tumor suppressor genes inactivated by epigenetic silencing and DNA methylation. We propose to expand this research by taking advantage of the newly developed International Mesothelioma Program (IMP) at the Brigham and Women's Hospital (BWH), where novel surgical treatment protocols have made possible for the first time investigation of tumor tissue from individuals with mesothelioma. We propose to test hypotheses positing that epigenetic inactivation of tumor suppressor genes, measured by assessing the DNA methylation profile, is associated with asbestos fiber type and burden. Further, we will test the hypothesis that the SV40 virus is involved in mesothelioma using a novel artifact resistant approach, and investigate the role of miRNAs in mesothelioma, asking if this might be a novel biomarker for this disease. Finally, we will test the hypothesis that survival in mesothelioma is associated with the individual molecular profile of the tumor. Our data will also be pooled with the expression profile data being generated at the BWH as part of the IMP, giving rise to a very rich repository of global genomic data for the exploratory analysis of the systems biology of malignant mesothelioma. In sum, we propose to continue to enroll and study patients referred to the BWH for new surgical treatments of this often fatal cancer. We will study the molecular character of their tumors, proposing that the character of the lesions in the tumor is associated with the nature of their asbestos exposure and well as with their response to treatment. Mesothelioma is a most often fatal cancer caused by asbestos exposure. We propose to study novel mechanisms of asbestos action in the body (including the inactivation and silencing of genes by induction of altered chromosome conformations), associating these with quantitative measures of asbestos exposure. This may help to explain, for example, why even small exposures ("doses") of asbestos pose a fatal cancer risk.