Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases

J Thorac Oncol. 2018 Jul;13(7):1022-1027. doi: 10.1016/j.jtho.2018.03.018. Epub 2018 Mar 29.


When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n = 4 [7.7%]) but a high number of EGFR mutations (n = 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain.

Keywords: EGFR; KRAS; Leptomeningeal metastases; Non–small cell lung cancer; Whole exome sequencing.

Publication types

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

MeSH terms

  • Biomarkers, Tumor / genetics
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary*
  • ErbB Receptors / genetics
  • Follow-Up Studies
  • Humans
  • Meningeal Neoplasms / genetics
  • Meningeal Neoplasms / pathology*
  • Mutation*
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Retrospective Studies
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics*


  • Biomarkers, Tumor
  • KRAS protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)