DNA evaluation of fragments for early interception (DELFI) of Lung cancer

项目摘要 血液中的无细胞DNA为癌症患者提供了一种非侵入性的诊断途径。我们的团体 已经开创了用于检测和表征癌症的液体活检方法。最近我们 开发了一种用于分析cfDNA片段化谱的全基因组方法，称为DELFI，DNA 评估碎片以便及早拦截。我们证明了健康的细胞的碎片分布， 来自低覆盖率全基因组测序的个体反映了白色血细胞的核小体模式， 而癌症患者具有改变的片段化谱。通过分析游离DNA 碎片模式，我们确定了局部癌症患者，这种早期检测工具可能导致 更好的病人结果。肺癌是世界上最致命的癌症，其发病率持续上升， 在全球范围内增加。目前迫切需要开发非侵入性方法， 改善对高风险个体的癌症筛查，并最终改善对普通人群的癌症筛查。一个明确 了解沿着肺肿瘤发生途径的分子变化对于鉴别 与致癌和肿瘤进展相关的生物标志物。用于早期检测的生物标志物开发 肺癌在筛查和鉴别良恶性方面具有广泛的临床应用 肺结节更好地非侵入性预测早期病变命运的工具对于 早期发现肺癌，此时治疗方法更有可能成功。不像有针对性的深 测序方法，这将是成本高昂的广泛使用的筛选人口，我们的方法 是负担得起的，高度可扩展的，并可能导致更有效的临床干预策略。近期 癌症基因组学与新型非侵入性血液检测的交叉可能会彻底改变癌症筛查。 我们的研究目的是研究游离DNA的起源和分子特征 沿着肺癌的进展，描绘这些癌前肺病变的变化 在可治疗的肺肿瘤中，以及在正常对照和良性肺肿瘤中， 病变我们的目标是实施新功能，以进一步优化血浆中的DELFI分子检测。的 一个计划是在累积样本和一个前瞻性肺癌样本中测试和验证我们的方法 筛查人群。最终，这种方法已经显示出作为泛癌症早期检测的巨大前景 战略，我们打算扩大我们的研究在这个方向上与其他EDRN中心合作。我们 我们设想这些分析将迅速转化为临床环境，提供新的非侵入性 早期癌症检测的方法。

Project Summary Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. Our groups have pioneered liquid biopsy approaches for detection and characterization of cancer. Recently we have developed a genome-wide approach for analysis of cfDNA fragmentation profiles called DELFI, DNA evaluation of fragments for early interception. We demonstrated that fragmentation profiles of healthy individuals from low coverage whole genome sequencing reflect nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. Through the analysis of cell-free DNA fragmentation patterns, we identified patients with localized cancer and this tool of early detection could result in better patient outcomes. Lung cancer is the most lethal cancer in the world, and its incidence continues to increase worldwide. There is an urgent, unmet clinical need for development of noninvasive approaches to improve cancer screening for high-risk individuals and ultimately the general population. A clear understanding of molecular changes along the pathway of lung tumorigenesis is critical for identifying biomarkers related to carcinogenesis and tumor progression. Biomarker development for early detection of lung cancer has broad clinical applications in screening as well as for distinguishing malignant from benign pulmonary nodules. Tools to better predict the fate of early lesions non-invasively would be invaluable for early detection of lung cancer, when curative approaches are more likely to succeed. Unlike targeted deep sequencing approaches that would be cost prohibitive for broad use in a screening population, our approach is affordable, highly scalable, and may lead to more effective strategies for clinical intervention. The recent intersection of cancer genomics with novel noninvasive blood tests could revolutionize cancer screening. The purpose of our proposed research is to study the origins and molecular characteristics of cell-free DNA fragments along the progression of Lung Cancer, profiling these alterations in preneoplastic lung lesions likely to progress to invasive cancer, and in treatable lung tumors, as well as in normal controls and in benign lesions. We aim to implement new features to further optimize our DELFI molecular test in plasma. The proposed plan is to test and validate our approach in both accrued samples and a prospective lung cancer screening population. Ultimately, this approach already shows great promise as a pan-cancer early detection strategy and we intend to expand our research in this direction in collaboration with other EDRN centers. We envision that these analyses will be rapidly translated into the clinical setting, providing new noninvasive approaches for early cancer detection.