Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases

J Neurooncol. 2016 May;128(1):93-100. doi: 10.1007/s11060-016-2081-5. Epub 2016 Mar 9.


Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

Keywords: Brain Tumor; Cell-free DNA; Cerebral spinal fluid; Droplet digital PCR; Exome sequencing; Leptomeningeal disease; Melanoma.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / cerebrospinal fluid*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary
  • DNA, Neoplasm / cerebrospinal fluid*
  • Disease Progression
  • Humans
  • Male
  • Melanoma / cerebrospinal fluid*
  • Melanoma / genetics
  • Melanoma / pathology
  • Meningeal Neoplasms / cerebrospinal fluid
  • Meningeal Neoplasms / genetics
  • Meningeal Neoplasms / pathology*
  • Middle Aged
  • PTEN Phosphohydrolase / genetics
  • Proto-Oncogene Proteins B-raf / genetics


  • DNA, Neoplasm
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase
  • PTEN protein, human