Lung Cancer Screening via Ultrasensitive and Cost-efficient Analysis of Tumor DNA Signatures in Blood

项目总结 通过开发更好的工具来检测隐匿性癌症，可以大幅提高癌症存活率 恶性肿瘤处于更早、更可治愈的阶段。不幸的是，识别血清蛋白质生物标记物的努力 具有足够的癌症特异性，可用于筛查，但收效甚微。在这里，我们追求一种 基于检测循环中异常肿瘤特异性突变DNA片段的替代策略 早期肺癌患者的比例。因为这些肿瘤衍生的DNA片段含有基因 在健康人中不常见的签名，它们在筛查应用程序中具有很大的前景 在这种情况下，高频率的假阳性结果是不可接受的。然而，这是一个艰巨的挑战。 为了建立一种能够检测微量突变DNA的检测方法，该DNA从一种 小的、早期的肿瘤，事先不知道肿瘤的突变情况。其他挑战包括 这是由经济因素以及健康人群中存在低水平突变造成的。至 为了应对这些挑战，我们组建了一支具有高度互补性的多学科团队 来自微软研究院、耶鲁大学、赖斯大学和哈佛大学。在这份提案中，我们描述了 创新的解决方案，我们应用生物化学、热力学、机器学习和 生物统计学开发和验证一种检测罕见突变DNA的超灵敏、经济高效的方法 血液中的碎片可作为早期肺癌的标志。

PROJECT SUMMARY Substantial improvements in cancer survival rates could be achieved by developing better tools to detect occult malignancies at an earlier, more curable stage. Unfortunately, efforts to identify serum protein biomarkers that are sufficiently cancer-specific to be used for screening have found little success. Here, we pursue an alternative strategy based on detection of exceptionally tumor-specific mutant DNA fragments in the circulation of patients with early-stage lung cancer. Because these tumor-derived DNA fragments harbor genetic signatures that would be uncommon in healthy individuals, they hold great promise for screening applications where a high frequency of false-positive results would be unacceptable. However, it is a formidable challenge to create an assay that is able to detect trace quantities of mutant DNA released into the bloodstream from a small, early-stage tumor, without knowing the tumor’s mutation profile beforehand. Additional challenges are posed by economic factors as well as the presence of low-level mutations in the healthy population. To address these challenges, we have assembled a multidisciplinary team with highly complementary expertise from Microsoft Research and from Yale, Rice, and Harvard Universities. In this proposal, we describe innovative solutions in which we apply tools of biochemistry, thermodynamics, machine learning, and biostatistics to develop and validate an ultrasensitive, cost-efficient assay for detecting rare mutant DNA fragments in blood as markers of early-stage lung cancer.