Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.
Nature communications. 2019 Oct 11*** epublish ***
Peter Ulz, Samantha Perakis, Qing Zhou, Tina Moser, Jelena Belic, Isaac Lazzeri, Albert Wölfler, Armin Zebisch, Armin Gerger, Gunda Pristauz, Edgar Petru, Brandon White, Charles E S Roberts, John St John, Michael G Schimek, Jochen B Geigl, Thomas Bauernhofer, Heinz Sill, Christoph Bock, Ellen Heitzer, Michael R Speicher
Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria., Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria., Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria., Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria., Freenome, South San Francisco, CA, USA., Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria., CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria. ., Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria. .