Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Viktor A. Adalsteinsson (), Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz (), J. Christopher Love () and Matthew Meyerson ()
Additional contact information
Viktor A. Adalsteinsson: Eli and Edythe L. Broad Institute of MIT and Harvard
Gavin Ha: Eli and Edythe L. Broad Institute of MIT and Harvard
Samuel S. Freeman: Eli and Edythe L. Broad Institute of MIT and Harvard
Atish D. Choudhury: Dana-Farber Cancer Institute
Daniel G. Stover: Dana-Farber Cancer Institute
Heather A. Parsons: Dana-Farber Cancer Institute
Gregory Gydush: Eli and Edythe L. Broad Institute of MIT and Harvard
Sarah C. Reed: Eli and Edythe L. Broad Institute of MIT and Harvard
Denisse Rotem: Eli and Edythe L. Broad Institute of MIT and Harvard
Justin Rhoades: Eli and Edythe L. Broad Institute of MIT and Harvard
Denis Loginov: Eli and Edythe L. Broad Institute of MIT and Harvard
Dimitri Livitz: Eli and Edythe L. Broad Institute of MIT and Harvard
Daniel Rosebrock: Eli and Edythe L. Broad Institute of MIT and Harvard
Ignaty Leshchiner: Eli and Edythe L. Broad Institute of MIT and Harvard
Jaegil Kim: Eli and Edythe L. Broad Institute of MIT and Harvard
Chip Stewart: Eli and Edythe L. Broad Institute of MIT and Harvard
Mara Rosenberg: Eli and Edythe L. Broad Institute of MIT and Harvard
Joshua M. Francis: Eli and Edythe L. Broad Institute of MIT and Harvard
Cheng-Zhong Zhang: Eli and Edythe L. Broad Institute of MIT and Harvard
Ofir Cohen: Eli and Edythe L. Broad Institute of MIT and Harvard
Coyin Oh: Eli and Edythe L. Broad Institute of MIT and Harvard
Huiming Ding: Massachusetts Institute of Technology
Paz Polak: Eli and Edythe L. Broad Institute of MIT and Harvard
Max Lloyd: Dana-Farber Cancer Institute
Sairah Mahmud: Dana-Farber Cancer Institute
Karla Helvie: Dana-Farber Cancer Institute
Margaret S. Merrill: Dana-Farber Cancer Institute
Rebecca A. Santiago: Dana-Farber Cancer Institute
Edward P. O’Connor: Dana-Farber Cancer Institute
Seong H. Jeong: Dana-Farber Cancer Institute
Rachel Leeson: Massachusetts Institute of Technology
Rachel M. Barry: Massachusetts Institute of Technology
Joseph F. Kramkowski: Dana-Farber Cancer Institute
Zhenwei Zhang: Dana-Farber Cancer Institute
Laura Polacek: Dana-Farber Cancer Institute
Jens G. Lohr: Eli and Edythe L. Broad Institute of MIT and Harvard
Molly Schleicher: Eli and Edythe L. Broad Institute of MIT and Harvard
Emily Lipscomb: Eli and Edythe L. Broad Institute of MIT and Harvard
Andrea Saltzman: Eli and Edythe L. Broad Institute of MIT and Harvard
Nelly M. Oliver: Dana-Farber Cancer Institute
Lori Marini: Dana-Farber Cancer Institute
Adrienne G. Waks: Dana-Farber Cancer Institute
Lauren C. Harshman: Dana-Farber Cancer Institute
Sara M. Tolaney: Dana-Farber Cancer Institute
Eliezer M. Van Allen: Eli and Edythe L. Broad Institute of MIT and Harvard
Eric P. Winer: Dana-Farber Cancer Institute
Nancy U. Lin: Dana-Farber Cancer Institute
Mari Nakabayashi: Dana-Farber Cancer Institute
Mary-Ellen Taplin: Dana-Farber Cancer Institute
Cory M. Johannessen: Eli and Edythe L. Broad Institute of MIT and Harvard
Levi A. Garraway: Eli and Edythe L. Broad Institute of MIT and Harvard
Todd R. Golub: Eli and Edythe L. Broad Institute of MIT and Harvard
Jesse S. Boehm: Eli and Edythe L. Broad Institute of MIT and Harvard
Nikhil Wagle: Eli and Edythe L. Broad Institute of MIT and Harvard
Gad Getz: Eli and Edythe L. Broad Institute of MIT and Harvard
J. Christopher Love: Eli and Edythe L. Broad Institute of MIT and Harvard
Matthew Meyerson: Eli and Edythe L. Broad Institute of MIT and Harvard

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00965-y

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