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（LDCT） 吸烟者可以更早发现肺癌，从而获得更有效的治疗。但决定哪些吸烟者应该 进行LDCT筛查是有争议的，而且可能有害。最近，美国预防服务工作组 （USPSTF）更新了他们对筛查的意见，建议对当前或最近的LDCT进行年度筛查。 吸烟者年龄在50岁至80岁之间，吸烟量为20包年（PY）或以上。此外他们 特别呼吁开发基于生物标志物的方法来预测谁将从筛查中受益。 精密表观遗传学可以回答这个问题。在2012年，我们发现在cg 05575921处的DNA甲基化， 芳烃受体阻遏物（AHRR）基因中的一个位点，可预测吸烟状况。从那时起，超过100 研究重复了这些发现。2018年，我们开发了Smoke Signature©，一个精确的，无参考的 甲基化敏感的数字PCR（MSdPCR）测定该基因座。在同行评议的出版物中，我们已经表明， 该测定的受试者操作特征（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每日消费量， 对戒烟的反应可用于监测戒烟治疗的成功。 有趣的是，在2017年，Bojesen及其同事发现，cg 05575921甲基化也预测了那些 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样本子集。特别是对于那些NLST 在报告戒烟的受试者中，我们的方法显著预测肺癌风险优于单独使用PY 不分种族和性别然而，我们的方法仅基于3200名NLST受试者的数据，所有 其中吸烟30 PY或更多。 在第二期计划中，我们建议完成对4800名非本地语文能力测试受试者的评估， > 30 PY的消耗和LDCT数据，然后使用来自NLST的仅X射线组中的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20 PY的卷烟消费量。 然后，我们将分析得到的数据，并开发一个种族和SES无偏倚的考克斯回归公式来预测 年龄在50-80岁之间且吸烟>20 PY的人群的风险。由此产生的实验室开发测试 (LDT)将在510 K批准的Bio-Rad QX-200平台上运行，试剂来自符合要求的公司 符合FDA标准。当实施时，该测试将降低医疗保健成本以及发病率和死亡率 不必要的程序。最终，我们相信这项测试将是必不可少的， 为所有吸烟者提供咨询和治疗监测。

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.