Highly personalized detection of minimal ewing sarcoma disease burden from plasma tumor DNA: Plasma tumor DNA in ewing sarcoma

Masanori Hayashi, David Chu, Christian F. Meyer, Nicolas J. Llosa, Gregory McCarty, Carol D. Morris, Adam Levin, Jean Paul Wolinsky, Catherine M. Albert, Diana A. Steppan, Ben Ho Park, David M. Loeb

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Background: Even though virtually all Ewing sarcoma patients achieve a radiographic complete response, up to 30% of patients who present with localized disease and up to 90% of those who present with metastases suffer a metastatic relapse, highlighting our inability to identify patients with residual disease at the end of therapy. Up to 95% of Ewing sarcomas carry a driving EWSETS translocation which has an intronic breakpoint that is specific to each tumor, and we developed a system to quantitatively detect the specific breakpoint DNA fragment in patient plasma. Methods: We used a long range multiplex PCR technique to identify tumor-specific EWS-ETS breakpoints in Ewing sarcoma cell lines, patient derived xenografts, and patient tumors, and this sequence was used to design tumor specific primer sets to detect plasma tumor DNA (ptDNA) by droplet digital PCR (ddPCR) in xenograft bearing mice and patients. Results: Tumor specific breakpoint DNA fragments were detected in the plasma of xenograft bearing mice, and signal correlated with tumor burden during primary tumor growth, following surgical resection, and upon metastatic relapse. Furthermore, we were able to detect the specific breakpoint in plasma DNA obtained from 3 patients with Ewing sarcoma, and in 2 patients, we were able to detect ptDNA when there was radiographically undetectable disease present. Conclusions: Use of ddPCR to detect tumor specific EWS-ETS fusion gene breakpoint ptDNA fragments can be developed into a highly personalized biomarker of relapse that can be optimized in animal studies for ultimate use in patients.

Original languageEnglish (US)
JournalCancer
Volume122
Issue number19
DOIs
StatePublished - 2016

Keywords

  • Cell free DNA
  • Circulating tumor DNA
  • EWS-FLI1
  • Metastasis
  • Plasma tumor DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hayashi, M., Chu, D., Meyer, C. F., Llosa, N. J., McCarty, G., Morris, C. D., Levin, A., Wolinsky, J. P., Albert, C. M., Steppan, D. A., Park, B. H., & Loeb, D. M. (2016). Highly personalized detection of minimal ewing sarcoma disease burden from plasma tumor DNA: Plasma tumor DNA in ewing sarcoma. Cancer, 122(19). https://doi.org/10.1002/cncr.30144