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

通过及早发现并实施以下措施，可大幅降低肺癌死亡率 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 与科罗拉多州肺孢子联合进行的一项研究，以前瞻性地评估一种肺炎支原体的痰中甲基化 预测肺癌的能力的一大组基因。这项嵌套的病例对照研究 科罗拉多州队列研究小组透露，一组基因可以预测3至18岁之间的肺癌发病率。 与临床诊断前几个月的敏感性和特异性均为%。相同的标记面板是 现在被用来评估流行的I期肺癌病例的痰中甲基化与 第二批高风险吸烟者。七个基因小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经确定 其他有希望进入肺癌早期检测终极小组的基因。这些研究 支持将甲基化基因小组推进到完全临床验证，作为早期检测的工具。这将是 通过与科罗拉多州孢子的合作，首先确定了 区分新诊断的I期肺癌和非癌症吸烟者。然后，我们将验证 使用前瞻性队列ACRIN进行肺癌早期检测的终极基因小组的性能 在国家肺部筛查试验中，肺癌高危人群被随机分配到肺部 癌症筛查方式。通过嵌套病例对照设计，敏感性、特异性、阳性和 这个基因小组的阴性预测值将被确定。这个项目的第二个主要目标是 与项目1密切合作，在该项目中，异常基因沉默的逆转正在作为一种 肺癌的治疗靶点。脱甲基剂5-氮杂胞苷的使用策略 组蛋白去乙酰酶抑制剂苯丁酸钠或MS275在 髓系恶性肿瘤的治疗。这种疗法在辅助环境中也可能有效，以防止 I期肺癌切除患者的肿瘤复发情况。通过与项目1的合作，我们将 用痰中基因甲基化作为预测肺部疗效和复发的生物标志物 接受去甲基化药物辅助治疗的I期肺癌患者中的癌症。 与公共卫生的相关性：这些研究最终应该导致开发一种经批准的 用于肺癌早期检测的诊断试验。此外，这些研究应该清楚地影响多早 通过创建一种基于分子的测试来指导治疗决定并提供 用于监测去甲基化治疗效果的生物标志物。

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.