Exome sequencing of cell-free DNA from metastatic cancer patients identifies clinically actionable mutations distinct from primary disease

Timothy M. Butler, Katherine Johnson-Camacho, Myron Peto, Nicholas J. Wang, Tara A. Macey, James Korkola, Theresa Koppie, Christopher Corless, Joe Gray, Paul Spellman

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of wholeexome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor.

Original languageEnglish (US)
Article numbere0136407
JournalPLoS One
Volume10
Issue number8
DOIs
StatePublished - Aug 28 2015

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Exome
Tumors
mutation
Mutation
neoplasms
DNA
Neoplasms
DNA Sequence Analysis
cells
Biopsy
sequence analysis
biopsy
lesions (animal)
metastasis
Neoplasm Metastasis
therapeutics
Precision Medicine
Aromatase
sarcoma
Sarcoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Exome sequencing of cell-free DNA from metastatic cancer patients identifies clinically actionable mutations distinct from primary disease. / Butler, Timothy M.; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J.; Macey, Tara A.; Korkola, James; Koppie, Theresa; Corless, Christopher; Gray, Joe; Spellman, Paul.

In: PLoS One, Vol. 10, No. 8, e0136407, 28.08.2015.

Research output: Contribution to journalArticle

Butler, Timothy M. ; Johnson-Camacho, Katherine ; Peto, Myron ; Wang, Nicholas J. ; Macey, Tara A. ; Korkola, James ; Koppie, Theresa ; Corless, Christopher ; Gray, Joe ; Spellman, Paul. / Exome sequencing of cell-free DNA from metastatic cancer patients identifies clinically actionable mutations distinct from primary disease. In: PLoS One. 2015 ; Vol. 10, No. 8.
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