A DNA Methylation Test for Guiding Lung Cancer Screening

肺癌夺去了15万美国人的生命，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。当控烟努力失败时，及早发现和治疗 肺癌的发病率是生存的最大希望。全国肺部筛查试验(NLST)招募了53,454人 报告吸烟史至少30年并显示LDCT筛查可预防 每1000名筛查对象中有3人死于肺癌，风险降低了16%。然而，近40%的LDCT 受试者的扫描异常，错误发现率为97%，使许多患者面临不必要的风险 额外的辐射暴露和侵入性诊断程序的并发症。 纳入DNA甲基化评估可能会通过以下方式改善LDCT筛查过程 为谁可能受益提供了更好的估计。简而言之，目前评估患者是否 需要LDCT，称为PLCOM2012模式，使用经常不可靠的变量自报香烟 消费。然而，行为诊断学已经开发出一种表观遗传学测试，它客观地确定了 吸烟强度。Bojesen和他的同事使用了一种类似的但不太精确的定量PCR分析方法进行了研究 哥本哈根城市研究中2576名符合LDCT筛查条件的吸烟者。他们发现DNA甲基化状态 在cg05575921，强烈预测了哪些吸烟者将从LDCT筛查中受益。事实上，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和 结果显示，在那些通常有资格接受LDCT筛查的人中，超过20%的人没有受益的前景 从放映中。 在这份R43提案中，我们将从NLST中测量3200名受试者的cg05575921甲基化并进行测试 将cg05575921甲基化状态纳入PLCOM2012肺癌风险模型是否会改善 预测。我们假设cg05575921上的DNA甲基化将预测肺癌的发生并确定 不太可能从LDCT筛查中受益的吸烟者群体。该项目将具有很高的商业价值 影响，因为它可能导致不必要的筛查显著减少。这支队伍资历很高。它是 由行为诊断公司的首席执行官领导，他发明了这种分析方法，公司控制着所有必要的知识产权。 他将得到杰夫·朗博士的协助，他是一位生物统计学家，在进行生物标记物方面享誉国际。 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。这是创新的，因为表观遗传 筛查对于癌症筛查来说是相对较新的。之所以可行，是因为DNA和临床信息 已经被收走了。如果成功，通往R44延长线并最终到达诊所的道路是清晰的 由于该分析已经在GMP条件下制造，所以数字PCR平台已经是510K 经批准，我们有合作者在FDA提交流程和经济驱动方面的经验 市场适应已经到位。

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.