The Epidemiology of Molecular Alterations in Mesothelioma

间皮瘤分子改变的流行病学

• 批准号: 7790575
• 负责人: Karl Timothy Kelsey
• 金额: $ 49.36万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-17 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790575
• 关键词: Address; Allelic Imbalance; Arts; Asbestos; Biological Markers; Cancer Etiology; Carcinogen exposure; Case Series; Cessation of life; Chromosomes; Clinical; Companions; Cost Sharing; DNA; DNA Methylation; Data; Developed Countries; Disease; Dose; Early treatment; Economic Burden; Economics; Enrollment; Epidemiologic Studies; Epigenetic Process; European; Exposure to; Fiber; Genetic; Genomics; Hospitals; Incidence; Individual; International; Investigation; Lesion; Litigation; Loss of Heterozygosity; Lung; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant mesothelioma; Measures; Mesothelioma; Methods; Methylation; MicroRNAs; Molecular; Molecular Conformation; Molecular Epidemiology; Molecular Profiling; Morphologic artifacts; Mutagens; Nature; Occupational Exposure; Operative Surgical Procedures; Patients; Pleura; Pleural Mesothelioma; Questionnaires; Research; Research Design; Research Infrastructure; Resistance; Resources; Risk Factors; Role; SV40 T Antigens; Sampling; Screening procedure; Simian virus 40; Source; Sum; Systems Biology; Testing; Time; Treatment Protocols; Trust; Tumor Suppressor Genes; Tumor Tissue; Tumor-Suppressor Gene Inactivation; United States; Viral; Virus; Woman; base; cancer risk; cost; gene induction; improved; indexing; novel; programs; remediation; repository; response; social; trend; tumor; virus genetics

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.

描述（由申请人提供）：长期以来，石棉暴露与胸膜间皮瘤有关。然而，石棉在诱导间皮瘤中的作用模式仍有待完全描述，并且对肿瘤抑制基因的表观遗传失活与致癌暴露之间的关系知之甚少。石棉不是直接作用的诱变剂，但具有致癌性；因此，人们也知道它会在接触者的肺部持续存在。我们的初步数据表明，石棉纤维负荷与表观遗传沉默和DNA甲基化使肿瘤抑制基因失活的数量显著相关。我们建议利用布里格姆妇女医院（BWH）新开发的国际间皮瘤项目（IMP）来扩大这项研究，在该项目中，新的手术治疗方案首次使间皮瘤患者肿瘤组织的研究成为可能。我们建议验证通过评估DNA甲基化谱测量的肿瘤抑制基因的表观遗传失活与石棉纤维类型和负担相关的假设。此外，我们将使用一种新的伪迹抗性方法来验证SV40病毒参与间皮瘤的假设，并研究mirna在间皮瘤中的作用，询问这是否可能是这种疾病的一种新的生物标志物。最后，我们将验证间皮瘤患者的生存与肿瘤的个体分子特征相关的假设。我们的数据还将与BWH生成的表达谱数据合并，作为IMP的一部分，为恶性间皮瘤系统生物学的探索性分析提供非常丰富的全球基因组数据存储库。总之，我们建议继续招募和研究转介到BWH的患者，以寻求新的手术治疗这种通常致命的癌症。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。间皮瘤是由接触石棉引起的最常见的致命癌症。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），并将这些机制与石棉暴露的定量测量联系起来。这可能有助于解释，例如，为什么即使很小的石棉暴露（“剂量”）也会造成致命的癌症风险。