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

一种改进的表观遗传算法用于指导低剂量 CT 肺癌筛查

基本信息

批准号：
10761599
负责人：
Kelsey Dawes
金额：
$ 88.56万
依托单位：
BEHAVIORAL DIAGNOSTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10761599
关键词：
Age Algorithms Area Under Curve Aryl Hydrocarbon Receptor Behavioral Biological Assay Biological Sciences Biopsy Cigarette Clinic Clinical Collection Colon Colon Carcinoma Consumption Counseling DNA DNA Methylation Data Detection Development Diagnostic Dose Educational Status Eligibility Determination Epigenetic Process Gender Genes Health Care Costs Intellectual Property International Investments Laboratories Lung Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Manufacturer Marketing Methods Methylation Monitor Morbidity - disease rate Ovarian Participant Patients Peer Review Persons Phase Production Property Rights Prostate Publications Publishing Race Radiation Radiation exposure Reagent Receiver Operating Characteristics Recommendation Recording of previous events Reporting Research Risk Roentgen Rays Running Saliva Site Smoke Smoker Smoking Smoking History Smoking Status Specimen Telemedicine Testing United States Preventative Services Task Force Unnecessary Procedures Update Work X-Ray Computed Tomography age effect arm base biomarker development biomarker identification cancer risk commercialization cost demethylation digital effective therapy high risk improved innovation low dose computed tomography lung cancer screening methylation testing mortality response risk prediction screening smoking cessation success tool

项目摘要

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.

具体目标大约 90% 的肺癌是由吸烟引起的。吸烟者可以更早地发现肺癌，从而获得更有效的治疗，但要确定哪些吸烟者应该接受治疗。进行 LDCT 筛查是有争议的，并且可能有害。最近，美国预防服务工作组提出了这一建议。 (USPSTF) 更新了他们关于筛查的意见，建议对当前或最近的年度 LDCT 筛查年龄在 50 岁至 80 岁之间、吸烟 20 包年 (PY) 或以上的吸烟者。特别呼吁开发基于生物标记的方法来预测谁将从筛查中受益。精密表观遗传学可能会回答这个问题，2012 年，我们发现了 cg05575921 处的 DNA 甲基化。芳基碳氢化合物受体阻遏物 (AHRR) 基因中的位点可预测吸烟状况，此后已有超过 100 种方法被用于预测吸烟状况。研究重复了这些发现。2018 年，我们开发了 Smoke Signature©，这是一种精确的、免费的参考。我们在同行评审出版物中展示了针对该位点的甲基化敏感数字 PCR (MSdPCR) 检测。该测定的受试者操作特征 (ROC) 曲线下面积 (AUC) 每日为 0.984 对于吸烟者来说，去甲基化的量可以准确预测每日的消费量，并且重新甲基化的量可以准确预测吸烟者的每日消费量。对戒烟的反应可用于监测戒烟治疗的成功。有趣的是，2017 年，Bojesen 及其同事表明，cg05575921 甲基化也预测了那些吸烟者可能受益于 LDCT 筛查最近，我们证实并扩展了这些发现。使用来自国家肺部筛查试验 (NLST) 的 DNA 样本子集，特别是对于那些 NLST。对于报告戒烟的受试者，我们的方法比单独使用 PY 更好地显着预测肺癌风险然而，我们的方法仅基于 3200 名 NLST 受试者的数据。其中吸烟 30 PY 或更多。在这个第二阶段项目中，我们建议完成对 4800 名 NLST 受试者的评估，所有受试者都具有 > 30 PY 的消耗和 LDCT 数据，然后使用来自 NLST 仅 X 射线组中 4800 名受试者的 DNA 和 PLCO 收集的 4800 名受试者将我们的测试范围扩大到 20 PY 的香烟消费量。然后，我们将分析结果数据并开发一个无种族和 SES 偏差的 Cox 回归公式来预测实验室开发了针对年龄在 50-80 岁且吸烟年数超过 20 年的人群的风险。 (LDT) 将在 510K 批准的 Bio-Rad QX-200 平台上运行，试剂来自符合要求的公司实施后，该测试将降低医疗费用以及发病率和死亡率。最终，我们相信这项测试对于预筛选至关重要。对所有吸烟者进行咨询和治疗监测。