Molecular Oncology (Aug 2020)

The effect of surgical trauma on circulating free DNA levels in cancer patients—implications for studies of circulating tumor DNA

  • Tenna V. Henriksen,
  • Thomas Reinert,
  • Emil Christensen,
  • Himanshu Sethi,
  • Karin Birkenkamp‐Demtröder,
  • Mikail Gögenur,
  • Ismail Gögenur,
  • Bernhard G. Zimmermann,
  • The IMPROVE Study Group,
  • Lars Dyrskjøt,
  • Claus L. Andersen

DOI
https://doi.org/10.1002/1878-0261.12729
Journal volume & issue
Vol. 14, no. 8
pp. 1670 – 1679

Abstract

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Detection of circulating tumor DNA (ctDNA) post‐treatment is an emerging marker of residual disease. ctDNA constitutes only a minor fraction of the cell‐free DNA (cfDNA) circulating in cancer patients, complicating ctDNA detection. This is exacerbated by trauma‐induced cfDNA. To guide optimal blood sample timing, we investigated the duration and magnitude of surgical trauma‐induced cfDNA in patients with colorectal or bladder cancer. DNA levels were quantified in paired plasma samples collected before and up to 6 weeks after surgery from 436 patients with colorectal cancer and 47 patients with muscle‐invasive bladder cancer. To assess whether trauma‐induced cfDNA fragments are longer than ordinary cfDNA fragments, the concentration of short ( 1 kb) fragments was determined for 91 patients. Previously reported ctDNA data from 91 patients with colorectal cancer and 47 patients with bladder cancer were used to assess how trauma‐induced DNA affects ctDNA detection. The total cfDNA level increased postoperatively—both in patients with colorectal cancer (mean threefold) and bladder cancer (mean eightfold). The DNA levels were significantly increased up to 4 weeks after surgery in both patient cohorts (P = 0.0005 and P ≤ 0.0001). The concentration of short, but not long, cfDNA fragments increased postoperatively. Of 25 patients with radiological relapse, eight were ctDNA‐positive and 17 were ctDNA‐negative in the period with trauma‐induced DNA. Analysis of longitudinal samples revealed that five of the negative patients became positive shortly after the release of trauma‐induced cfDNA had ceased. In conclusion, surgery was associated with elevated cfDNA levels, persisting up to 4 weeks, which may have masked ctDNA in relapse patients. Trauma‐induced cfDNA was of similar size to ordinary cfDNA. To mitigate the impact of trauma‐induced cfDNA on ctDNA detection, it is recommended that a second blood sample collected after week 4 is analyzed for patients initially ctDNA negative.

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