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

Author

Listed:
  • Viktor A. Adalsteinsson

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • Gavin Ha

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Samuel S. Freeman

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Atish D. Choudhury

    (Dana-Farber Cancer Institute)

  • Daniel G. Stover

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Heather A. Parsons

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • 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
    Massachusetts Institute of Technology)

  • Dimitri Livitz

    (Eli and Edythe L. Broad Institute of MIT and Harvard)

  • Daniel Rosebrock

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Harvard Medical School)

  • 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
    Dana-Farber Cancer Institute)

  • Cheng-Zhong Zhang

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Ofir Cohen

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • 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
    Harvard Medical School
    Massachusetts General Hospital)

  • 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
    Dana-Farber Cancer Institute)

  • 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
    Brigham and Women’s Hospital)

  • 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
    Dana-Farber Cancer Institute
    Harvard Medical School
    Brigham and Women’s Hospital)

  • Eric P. Winer

    (Dana-Farber Cancer Institute)

  • Nancy U. Lin

    (Dana-Farber Cancer Institute)

  • Mari Nakabayashi

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • 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
    Dana-Farber Cancer Institute
    Harvard Medical School
    Brigham and Women’s Hospital)

  • Todd R. Golub

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School
    Howard Hughes Medical Institute)

  • 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
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Gad Getz

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • J. Christopher Love

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • Matthew Meyerson

    (Eli and Edythe L. Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School
    Brigham and Women’s Hospital)

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.

Suggested Citation

  • 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 & , 2017. "Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00965-y
    DOI: 10.1038/s41467-017-00965-y
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