P2: Gene Promoter Hypermethylation as a Biomarker for Lung Cancer Detection

P2：基因启动子高甲基化作为肺癌检测的生物标志物

• 批准号: 7567919
• 负责人: Steven A Belinsky
• 金额: $ 79.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7567919
• 关键词: Adjuvant; American College of Radiology Imaging Network; Azacitidine; Biological Markers; Cancer Detection; Cancer Patient; Chemoprevention; Clinical; Clinical Trials; Collaborations; Colorado; Development; Diagnostic; Diagnostic Neoplasm Staging; Diagnostic tests; Disease; Early Diagnosis; Early treatment; Effectiveness; Epidemiology; Epigenetic Process; Evaluation; Gene Silencing; Genes; Goals; Histone Deacetylase Inhibitor; Hypermethylation; Incidence; Institution; Intervention; Lead; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modality; Modeling; Molecular; Monitor; Mus; Myeloproliferative disease; Nested Case-Control Study; Newly Diagnosed; Performance; Persons; Phase; Predictive Value; Prevention; Prevention therapy; Prospective Studies; Public Health; Randomized; Recurrence; Recurrent Malignant Neoplasm; Reproduction spores; Research Personnel; Resected; Risk; Screening procedure; Selenium; Sensitivity and Specificity; Smoker; Sodium phenylbutyrate; Specificity; Sputum; Staging; Syndrome; Testing; Therapeutic; Thoracic Radiography; Validation; Work; base; cancer recurrence; case control; clinical Diagnosis; cohort; demethylation; design; effective therapy; follow-up; high risk; lung cancer screening; mortality; prevent; promoter; prospective; response; therapeutic target; tool; tumor

Mortality from lung cancer could be reduced substantially through early detection and the implementation of targeted approaches for chemoprevention and treatment of early stage cancers. We conducted the first study in collaboration with the Colorado Lung SPORE to prospectively evaluate methylation in sputum of a large panel of genes for their ability to predict lung cancer. This nested, case-control study of persons from the Colorado Cohort revealed that a panel of genes could predict incident lung cancer between 3 and 18 months prior to clinical diagnosis with both a sensitivity and specificity of 64%. This same marker panel is now being used to evaluate methylation in sputum from prevalent stage I lung cancer cases compared to a second cohort of high-risk smokers. Methylation of three or more genes of a seven-gene panel revealed a sensitivity of 75% and a specificity of 81%. Evaluation of additional candidate biomarkers has identified other promising genes for inclusion in the ultimate panel for early detection of lung cancer. These studies support advancing a methylation gene panel to full clinical validation as a tool for early detection. This will be accomplished through collaboration with the Colorado SPORE by first determining the optimal gene panel for distinguishing newly diagnosed stage I lung cancer from cancer-free smokers. We will then validate the performance of the ultimate gene panel for early detection of lung cancer using ACRIN, a prospective cohort of people at high risk for lung cancer within the National Lung Screening Trial who are randomized to lung cancer screening modalities. Through a nested, case-control design, the sensitivity, specificity, positive, and negative predictive values of this gene panel will be determined. A second major goal for this project is to collaborate closely with Project 1 in which the reversal of abnormal gene silencing is being tested as a therapeutic target for lung cancer. The strategy of using the demethylating agent 5-azacytidine and the histone deacetylase inhibitors, sodium phenylbutyrate or MS275 has shown promising responses in the treatment of myeloid malignancies. This therapy may also be effective in an adjuvant setting to prevent recurrence of cancer in resected stage I lung cancer patients. Through collaboration with Project 1, we will use gene methylation in sputum as a biomarker to predict therapeutic response and recurrence of lung cancer in resected stage I lung cancer patients receiving adjuvant treatment with demethylating agents. Relevance to Public Health: These studies should ultimately lead to the development of an approved diagnostic test for early detection of lung cancer. In addition, these studies should clearly impact how early stage lung cancer is managed by creating a molecular-based test to guide treatment decisions and provide biomarkers for monitoring the efficacy of demethylation therapy.

通过早期发现和实施以下措施可以大大降低肺癌死亡率 早期癌症的化学预防和治疗的有针对性的方法。我们进行了第一次 与科罗拉多肺孢子合作的研究前瞻性评估痰液中的甲基化 一大组基因具有预测肺癌的能力。这项巢式病例对照研究的对象是来自 科罗拉多队列研究表明，一组基因可以预测 3 岁至 18 岁之间发生的肺癌 临床诊断前几个月，敏感性和特异性均为 64%。这个相同的标记面板是 现在用于评估流行的 I 期肺癌病例的痰液甲基化情况，并与 第二组高危吸烟者。七基因组中三个或更多基因的甲基化揭示了 敏感性为 75%，特异性为 81%。对其他候选生物标志物的评估已确定 其他有前途的基因将被纳入肺癌早期检测的最终组中。这些研究 支持将甲基化基因组推进全面临床验证，作为早期检测的工具。这将是 通过与科罗拉多 SPORE 合作，首先确定最佳基因组 区分新诊断的 I 期肺癌和无癌吸烟者。然后我们将验证 使用前瞻性队列 ACRIN 进行肺癌早期检测的最终基因组的性能 在国家肺部筛查试验中，肺癌高危人群被随机分为肺癌组 癌症筛查方式。通过嵌套的病例对照设计，敏感性、特异性、阳性和 将确定该基因组的阴性预测值。该项目的第二个主要目标是 与项目 1 密切合作，其中正在测试异常基因沉默的逆转 肺癌的治疗靶点。使用去甲基化剂5-氮杂胞苷的策略及 组蛋白脱乙酰酶抑制剂、苯丁酸钠或 MS275 在 治疗骨髓恶性肿瘤。这种疗法在辅助环境中也可能有效预防 已切除的 I 期肺癌患者的癌症复发。通过与项目1的合作，我们将 使用痰中的基因甲基化作为生物标志物来预测肺癌的治疗反应和复发 接受去甲基化药物辅助治疗的已切除的 I 期肺癌患者的癌症。 与公共卫生的相关性：这些研究最终应导致开发出经批准的 早期发现肺癌的诊断测试。此外，这些研究应该清楚地影响多久 分期肺癌的管理是通过创建基于分子的测试来指导治疗决策并提供 用于监测去甲基化治疗疗效的生物标志物。