Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
Author(s)Ha, Gavin; Freeman, Samuel S.; Choudhury, Atish D.; Stover, Daniel G.; Parsons, Heather A.; Gydush, Gregory; Reed, Sarah C.; Rotem, Denisse; Rhoades, Justin; Livitz, Dimitri; Rosebrock, Daniel; Leshchiner, Ignaty; Kim, Jaegil; Stewart, Chip; Rosenberg, Mara; Francis, Joshua M.; Zhang, Cheng-Zhong; Cohen, Ofir; Oh, Coyin; Polak, Paz; Lloyd, Max; Mahmud, Sairah; Helvie, Karla; Merrill, Margaret S.; Santiago, Rebecca A.; O’Connor, Edward P.; Jeong, Seong H.; Kramkowski, Joseph F.; Zhang, Zhenwei; Polacek, Laura; Lohr, Jens G.; Schleicher, Molly; Lipscomb, Emily; Saltzman, Andrea; Oliver, Nelly M.; Marini, Lori; Waks, Adrienne G.; Harshman, Lauren C.; Tolaney, Sara M.; Van Allen, Eliezer M.; Winer, Eric P.; Lin, Nancy U.; Nakabayashi, Mari; Taplin, Mary-Ellen; Johannessen, Cory M.; Garraway, Levi A.; Golub, Todd R.; Boehm, Jesse S.; Wagle, Nikhil; Getz, Gad; Meyerson, Matthew; Adalsteinsson, Viktor A.; Loginov, Denis; Ding, Huiming; Leeson, Rachel; Barry, Rachel M; Love, John C; ... Show more Show less
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Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Chemical Engineering
Nature Publishing Group
Adalsteinsson, Viktor A. et al. “Scalable Whole-Exome Sequencing of Cell-Free DNA Reveals High Concordance with Metastatic Tumors.” Nature Communications 8, 1 (November 2017): 1324 © 2017 The Author(s)
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