An Improved Epigenetic Algorithm for Guiding Low Dose CT Lung Cancer Screening

具体目标 大约90%的肺癌是由吸烟引起的。低剂量CT扫描(LDCT) 吸烟者可以更早地发现肺癌，从而获得更有效的治疗。但确定哪些吸烟者应该 进行LDCT筛查是有争议的，而且具有潜在的危害。最近，美国预防服务工作组 (USPSTF)更新了他们对筛查的意见，以建议当前或最近的年度LDCT筛查 年龄在50到80岁之间的吸烟者，吸烟年限在20包(PY)或以上。此外，他们还 特别呼吁开发基于生物标记物的方法，以预测谁将从筛查中受益。 精密表观遗传学可能会回应这一呼吁。2012年，我们发现了cg05575921的DNA甲基化。 芳香烃受体阻滞剂(AHRR)基因中的位置，预测吸烟状态。从那时起，超过100人 研究已经重复了这些发现。2018年，我们开发了Smoke Signature©，一种精确的、免参考的 甲基化敏感的数字聚合酶链式反应(MSdPCR)分析该基因座。在同行评议的出版物中，我们已经表明 每天的受试者操作员特征(ROC)曲线下面积(AuC)为0.984 吸烟者，去甲基化的数量准确地预测了日常消费，并且重新甲基化 戒烟反应可用于监测戒烟治疗的成功与否。 有趣的是，在2017年，Bojesen和他的同事们表明，cg05575921甲基化也可以预测 吸烟者可能受益于LDCT筛查。最近，我们现在已经证实并扩展了这些发现 使用来自国家肺筛查试验(NLST)的DNA样本的子集。尤其是对于那些NLST 报告戒烟的受试者，我们的方法比单独使用PY更能预测肺癌风险 以不分种族和性别的方式。然而，我们的方法仅基于3200名NLST受试者的数据，所有 其中吸烟30支或更多的人。 在这项第二阶段计划中，我们建议完成对4800名NLST受试者的评估，这些受试者都有 &gt；30Py的消耗和LDCT数据，然后在NLST的仅X光臂中使用4800名受试者的DNA 从PLCO收集的4800名受试者中，将我们的测试范围扩展到香烟消费的20年。 然后我们将分析结果数据，并开发出一个无种族和SES偏差的COX回归公式来预测 年龄在50-80岁和吸烟年限在20岁之间的人的风险。由此产生的实验室开发了测试 (LDT)将在510K批准的Bio-Rad QX-200平台上运行，其试剂来自符合要求的公司 符合FDA的标准。一旦实施，这项测试将降低医疗成本、发病率和死亡率 避免不必要的程序。最终，我们相信这项测试对于两种预筛选都是必不可少的 对所有吸烟者进行咨询和治疗监测。

SPECIFIC AIMS Approximately 90% of lung cancer results from smoking. Low Dose Computerized Tomography (LDCT) of smokers can detect lung cancer earlier allowing more effective treatment. But determining which smokers should get LDCT screening is controversial and potentially harmful. Recently, the U.S Preventive Services Task Force (USPSTF) updated their opinion on screening to recommend annual LDCT screening for current or recent smokers between the ages of 50 and 80 who have smoked 20 pack years (PY) or more. In addition, they specifically called for the development of biomarker-based methods to predict who will benefit from screening. Precision Epigenetics may answer this call. In 2012, we showed that DNA methylation at cg05575921, a site in the aryl hydrocarbon receptor repressor (AHRR) gene, predicts smoking status. Since then, over 100 studies have replicated those findings. In 2018, we developed Smoke Signature©, a precise, reference free methylation sensitive digital PCR (MSdPCR) assay for this locus. In peer-reviewed publications, we have shown that the Receiver Operator Characteristic (ROC) area under the curve (AUC) for this assay is 0.984 for daily smokers, the amount of demethylation accurately predicts daily consumption and that the re-methylation response to smoking cessation can be used to monitor success of cessation therapy. Intriguingly, in 2017, Bojesen and colleagues showed that cg05575921 methylation also predicts those smokers likely to benefit from LDCT screening. Recently, we have now confirmed and extended these findings using a subset of DNA specimens from the National Lung Screening Trial (NLST). In particular for those NLST subjects who reported quitting smoking, our method significantly predicts lung cancer risk better than PY alone in a racial and gender-free manner. However, our method is based only the data from 3200 NLST subjects, all of whom smoked 30 PY or more. In this Phase II project, we propose to finish our assessments of the 4800 NLST subjects, all of whom have > 30 PY of consumption and LDCT data, then use DNA from 4800 subjects in x-ray only arm of the NLST and 4800 subjects from the PLCO collection to extend the range of our test down to 20 PY of cigarette consumption. We will then analyze the resulting data and develop a race and SES bias free Cox regression formula to predict risk for those between the ages of 50-80 years and >20 PY of smoking. The resulting laboratory developed test (LDT) will run on the 510K approved Bio-Rad QX-200 platform with reagents from companies that can comply with FDA standards. When implemented, the test will decrease healthcare costs and morbidity and mortality from unnecessary procedures. Eventually, we believe that this test will be essential for both prescreening counselling and treatment monitoring of all smokers.