A DNA Methylation Test for Guiding Lung Cancer Screening

指导肺癌筛查的 DNA 甲基化测试

• 批准号: 10242473
• 负责人: Robert A Philibert
• 金额: $ 39.56万
• 依托单位: BEHAVIORAL DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242473
• 关键词: American; American College of Radiology Imaging Network; Automobile Driving; Behavioral; Biological Assay; Biological Markers; Biomedical Engineering; Biopsy; Blood; Businesses; Cessation of life; Cigarette; Cities; Clinic; Clinical; Consumption; DNA; DNA Methylation; Data; Data Analyses; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Early Diagnosis; Early treatment; Economics; Enrollment; Epigenetic Process; Ethicists; Goals; Health Expenditures; Intellectual Property; International; Lead; Lung; Malignant neoplasm of lung; Measures; Medical; Methods; Methylation; Modeling; Morbidity - disease rate; Pathway interactions; Patient Self-Report; Patients; Population; Process; Radiation exposure; Randomized; Recording of previous events; Regression Analysis; Reporting; Risk; Risk Factors; Risk Reduction; Saliva; Sampling; Scanning; Scientist; Screening for cancer; Secondary to; Smoker; Smoking; Smoking History; Testing; arm; base; cancer risk; computed tomography screening; digital; epigenetic marker; experience; improved; innovation; low dose computed tomography; lung cancer screening; lung imaging; member; methylation testing; mortality; prevent; repository; risk prediction; screening; screening program; tobacco control

Lung cancer kills 150,000 Americans and is responsible for 150 billion dollars of economic damage annually. The largest risk factor for lung cancer is smoking. When tobacco control efforts fail, early detection and treatment of lung cancer offer the best hope for survival. The National Lung Screening Trial (NLST) enrolled 53,454 subjects who reported a cigarette history of at least 30 pack years and showed that LDCT screening prevented 3 lung cancer deaths for every 1,000 screened subjects, a 16% risk reduction. However, nearly 40% of LDCT subjects had an abnormal scan with a false discovery rate of 97%, placing many patients at risk for unnecessary additional radiation exposure and complications from invasive diagnostic procedures. The incorporation of DNA methylation assessments may improve the LDCT screening process by providing a better estimate of who may benefit. In brief, the current method for evaluating whether a patient needs LDCT, referred to as the PLCOM2012 mode, uses the often-unreliable variable of self-reported cigarette consumption. However, Behavioral Diagnostics has developed an epigenetic assay that objectively determines smoking intensity. Using a similar, yet less precise quantitative PCR assay, Bojesen and colleagues studied 2,576 LDCT screening-eligible smokers in the Copenhagen City Study. They found that DNA methylation status at cg05575921 strongly predicted which smokers would benefit from LDCT screening. Indeed, in their study, this epigenetic marker of smoking outperformed the entire PLCOM2012 model in predicting cancer risk and showed that over 20% of those who would normally qualify for LDCT screening had no prospect of benefitting from screening. In this R43 proposal, we will measure cg05575921 methylation in 3200 subjects from the NLST and test whether incorporating cg05575921 methylation status into the PLCOM2012 lung cancer risk model improves prediction. We hypothesize that DNA methylation at cg05575921 will predict lung cancer occurrence and identify a population of smokers who are unlikely to benefit from LDCT screening. This project will have high commercial impact because it may lead to a marked decrease in unnecessary screening. The team is highly qualified. It is led by the CEO of Behavioral Diagnostics who invented the assay and the company controls all necessary IP. He will be assisted by Dr. Jeff Long, a biostatistician with an international reputation for conducting biomarker analyses, and a team of pulmonologists, ethicists and other scientists. It is innovative because epigenetic screening is relatively new to cancer screening. It is feasible because the DNA and clinical information has already been collected. If successful, the pathway to the R44 extension, and eventually the clinic, is clear-cut because the assay is already manufactured under GMP conditions, the digital PCR platform is already 510K approved, we have collaborators have experience with the FDA submission process, and the economics driving market adaption are already in place.

肺癌导致15万美国人死亡，每年造成1500亿美元的经济损失。 肺癌的最大危险因素是吸烟。当烟草控制努力失败时，早期发现和治疗 是最有希望存活下来的国家肺筛查试验（NLST）招募了53，454人 报告至少30包年吸烟史并显示LDCT筛查可预防 每1,000名筛查受试者中有3人死于肺癌，风险降低16%。然而，近40%的LDCT 受试者有异常扫描，错误发现率为97%，使许多患者处于不必要的风险中。 额外的辐射暴露和侵入性诊断程序的并发症。 DNA甲基化评估的结合可以通过以下方式改善LDCT筛查过程： 从而更好地估计谁可能受益。简而言之，目前用于评估患者是否 需要LDCT，称为PLCOM 2012模式，使用自我报告的香烟这一经常不可靠的变量 消费然而，行为诊断已经开发了一种表观遗传分析， 吸烟强度Bojesen及其同事使用类似但不太精确的定量PCR检测方法， 哥本哈根城市研究中有2,576名符合LDCT筛查条件的吸烟者。他们发现DNA甲基化状态 cg 05575921强烈预测了哪些吸烟者将受益于LDCT筛查。在他们的研究中， 这种吸烟的表观遗传标记在预测癌症风险方面优于整个PLCOM 2012模型， 显示超过20%的正常有资格进行LDCT筛查的人没有受益的前景 从筛选。 在这项R43提案中，我们将测量来自NLST的3200名受试者的cg 05575921甲基化，并测试 将cg 05575921甲基化状态纳入PLCOM 2012肺癌风险模型是否改善了 预测.我们假设cg 05575921的DNA甲基化可以预测肺癌的发生， 不太可能从LDCT筛查中获益的吸烟人群。该项目将具有很高的商业价值。 因为它可能导致不必要的筛选显着减少。团队素质很高。是 由行为诊断公司的首席执行官领导，他发明了检测方法，公司控制着所有必要的知识产权。 他将得到Jeff Long博士的协助，Jeff Long博士是一位生物统计学家，在进行生物标志物方面享有国际声誉。 分析，以及一个由肺病学家、伦理学家和其他科学家组成的团队。它之所以具有创新性， 筛查对于癌症筛查来说是相对较新的。这是可行的，因为DNA和临床信息 已收集。如果成功的话，通往R44延伸的道路，以及最终的临床，是明确的。 由于该检测试剂盒已经在GMP条件下生产，因此数字PCR平台已经是510 K 批准，我们的合作者有经验的FDA提交过程，和经济驱动 市场的适应已经到位。