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Nat Commun. 2017 Nov 6;8(1):1324. doi: 10.1038/s41467-017-00965-y.

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

Author information

1
Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA. viktor@broadinstitute.org.
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, 02142, MA, USA. viktor@broadinstitute.org.
3
Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA.
4
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, 02215, MA, USA.
5
Harvard Medical School, 250 Longwood Avenue, Boston, 02115, MA, USA.
6
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, 02142, MA, USA.
7
Massachusetts General Hospital, 55 Fruit Street, Boston, 02129, MA, USA.
8
Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, MA, USA.
9
Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 20815, MD, USA.
10
Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA. gadgetz@broadinstitute.org.
11
Harvard Medical School, 250 Longwood Avenue, Boston, 02115, MA, USA. gadgetz@broadinstitute.org.
12
Massachusetts General Hospital, 55 Fruit Street, Boston, 02129, MA, USA. gadgetz@broadinstitute.org.
13
Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA. clove@mit.edu.
14
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, 02142, MA, USA. clove@mit.edu.
15
Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA. matthew_meyerson@dfci.harvard.edu.
16
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, 02215, MA, USA. matthew_meyerson@dfci.harvard.edu.
17
Harvard Medical School, 250 Longwood Avenue, Boston, 02115, MA, USA. matthew_meyerson@dfci.harvard.edu.
18
Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, MA, USA. matthew_meyerson@dfci.harvard.edu.

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.

PMID:
29109393
PMCID:
PMC5673918
DOI:
10.1038/s41467-017-00965-y
[Indexed for MEDLINE]
Free PMC Article

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