Genetic and Epigenetic Biomarkers for SCC of the Lung

肺鳞状细胞癌的遗传和表观遗传生物标志物

• 批准号: 7686926
• 负责人: Steven A Belinsky
• 金额: $ 67.19万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686926
• 关键词: Adenocarcinoma; Affect; Alpha Particles; Apoptosis; Biological Markers; Bleomycin; CDKN2A gene; Cancer Etiology; Carcinogens; Carcinoma; Cell Cycle; Cell Cycle Regulation; Cell Line; Cessation of life; Chromosome abnormality; Chronic Obstructive Airway Disease; Clinical; CpG Islands; DNA; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA-dependent protein kinase; Development; Disease; Dose; Double Strand Break Repair; Early Diagnosis; Environmental Carcinogens; Epigenetic Process; Epithelial Cells; Etiology; Exposure to; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genomics; Germ Lines; Growth; Haplotypes; High Prevalence; Histologic; Hypermethylation; In Vitro; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methylation; Mining; Mission; National Institute of Environmental Health Sciences; Neoplastic Cell Transformation; Nested Case-Control Study; Nucleotide Excision Repair; Pathway interactions; Plutonium; Predisposition; RNA Interference; Radon; Regulator Genes; Risk; Risk Assessment; Risk Factors; Role; Scanning; Screening procedure; Single Nucleotide Polymorphism; Smoker; Smoking History; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Staging; Testing; Time; Tobacco; Tumor Suppressor Genes; Uranium; Variant; Woman; base; benzo(a)pyrene diolepoxide I; case control; cell transformation; cohort; indium-bleomycin; knock-down; lung cancer screening; men; novel; population based; prevent; promoter; prospective; public health relevance; repaired; response

DESCRIPTION (provided by applicant): Studies in this application will test the hypothesis that variation in susceptibility for developing lung cancer is mediated by germ-line polymorphisms in DNA repair genes that compromise repair capacity. This damage in turn leads to the acquisition of epigenetic changes in the form of aberrant gene promoter hypermethylation in critical regulatory genes and malignant transformation. This hypothesis will be tested through four specific aims. In Aim 1 siRNA will be used to reduce expression of genes involved in the nonhomologous recombination and nucleotide excision repair pathways in immortalized bronchial epithelial cells. The effect of reduced gene expression will be assessed by quantifying chromosome aberrations formed following exposure to carcinogens that induce either single- (BPDE1) or double-strand breaks (bleomycin) in DNA. In Aim 2 immortalized bronchial epithelial cell lines with stable knock down of genes found to effect DNA repair capacity (DRC) will be exposed chronically to BPDE1 or bleomycin. Time to transformation and genes inactivated by methylation in these cell lines will be defined and compared to repair competent cell lines. In Aim 3 a nested, case-control study of squamous cell carcinoma (SCC) will be conducted in 1440 radon-exposed uranium miners. Genes identified in Aim 1 to affect DRC will be studied. Global association of each selected locus with SCC risk will be studied using a haplotype approach. Risk variants will be defined and the association of radon dose between cases and controls with specific risk variants investigated. Aim 4 will focus on the elucidation of genes and pathways involved in the development of SCC and whether the genes affected by methylation differ as a function of radon exposure. These studies are relevant to the mission of the NIEHS and NCI: they will uncover the contribution of single- and double-strand break DNA damage associated with environmental carcinogens to lung cancer and identify biomarkers for risk assessment and early detection of lung cancer, the leading cause of cancer-related death in the U.S. PUBLIC HEALTH RELEVANCE: Studies in this application will identify biomarkers for risk (DNA repair genes) and early detection (methylated genes) of lung cancer. Population-based screening studies will then be conducted to evaluate the ability of the biomarker to detect early lung cancer. Ultimately approaches could be developed that modify the activity of the affected genes to prevent or treat lung cancer. 7. Project Narrative These studies will identify biomarkers for risk (DNA repair genes) and early detection (methylated genes) of lung cancer. Population-based screening studies will then be conducted to evaluate the ability of the biomarker to detect early lung cancer. Ultimately approaches could be developed that modify the activity of the affected genes to prevent or treat lung cancer.

描述（由申请人提供）：本申请中的研究将检验以下假设：罹患肺癌的易感性变化是由损害修复能力的 DNA 修复基因的种系多态性介导的。这种损伤反过来导致关键调控基因中异常基因启动子高甲基化和恶性转化形式的表观遗传变化。这一假设将通过四个具体目标进行检验。目标 1 siRNA 将用于减少永生化支气管上皮细胞中参与非同源重组和核苷酸切除修复途径的基因表达。基因表达减少的影响将通过量化暴露于诱发 DNA 单链 (BPDE1) 或双链断裂 (博来​​霉素) 的致癌物质后形成的染色体畸变来评估。在目标 2 中，稳定敲除影响 DNA 修复能力 (DRC) 的基因的永生化支气管上皮细胞系将长期暴露于 BPDE1 或博莱霉素。将定义这些细胞系中的转化时间和甲基化失活的基因，并与修复感受态细胞系进行比较。在目标 3 中，将对 1440 名接触氡气的铀矿工人进行鳞状细胞癌 (SCC) 的巢式病例对照研究。将研究目标 1 中确定的影响 DRC 的基因。将使用单倍型方法研究每个选定基因座与 SCC 风险的整体关联。将定义风险变异，并调查病例和对照之间的氡剂量与特定风险变异的关联。目标 4 将重点阐明参与 SCC 发展的基因和途径，以及受甲基化影响的基因是否因氡暴露的函数而有所不同。这些研究与 NIEHS 和 NCI 的使命相关：他们将揭示与环境致癌物相关的单链和双链 DNA 断裂损伤对肺癌的影响，并确定用于肺癌风险评估和早期检测的生物标志物。美国癌症相关死亡的原因 公共卫生相关性：本申请中的研究将确定肺癌风险（DNA 修复基因）和早期检测（甲基化基因）的生物标志物。然后将进行基于人群的筛查研究，以评估生物标志物检测早期肺癌的能力。最终可以开发出改变受影响基因活性的方法来预防或治疗肺癌。 7. 项目叙述这些研究将确定肺癌风险（DNA 修复基因）和早期检测（甲基化基因）的生物标志物。然后将进行基于人群的筛查研究，以评估生物标志物检测早期肺癌的能力。最终可以开发出改变受影响基因活性的方法来预防或治疗肺癌。