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

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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.