Cerebrospinal Fluid Cell Free DNA Demonstrates Unique Genomic Alterations in Non-Small Cell Lung Cancer with Leptomeningeal Metastasis

Background: We retrospectively reported unique molecular features of cerebrospinal fluid(CSF) of NSCLC patients with LM, suggesting to establish CSF as a better liquid biopsy method in clinical practices. Methods: We performed next-generation panel sequencing of primary tumor tissue, plasma and cerebrospinal fluid (CSF) from 131 NSCLC patients with LM. Findings: High somatic copy number variations (CNV) were observed in CSF compared with plasma and primary tumor, exhibiting unique molecular features of CSF of NSCLC patients with LM. The status of EGFR-activating mutations was highly concordant between CSF, plasma, and primary tumors. There was no statistical difference between CSF, plasma and tumor tissues to detect EGFR mutation. ALK translocation was detected in 8.3% of tumor tissues, but detection rate was only 2.4% in CSF and 2.7% in plasma. Except EGFR and ALK, other rare driver genes such as ROS1 rearrangement, RET fusion, HER2 mutation, NTRK1 fusion, and BRAF V600E mutation were detected in 7.9% of CSF and 11.1% of tumor tissues, but only 4% in plasma. Except EGFR, TP53 and RB1 aberrations were high in these patients with CSF and primary tumor samples, implicating a prediction of high LM risk. Interestingly, co-occurring of EGFR and TP53 was not different among CSF, plasma and tumor tissues. However, co-occurring of EGFR and RB1 and EGFR/TP53/RB1 were higher in CSF compared with plasma or tumor tissues. Interpretation: Our study has shed light on the unique genomic variations of CSF and demonstrated that CSF may represent better liquid biopsy for NSCLC patients with LM. Funding Statement: This study was funded by the grants from the National Young 1000 Talents Program of China and Jiangsu Province Education Department, Jiangsu Province “Innovative and Entrepreneurial Team” and “Innovative and Entrepreneurial Talent.” Declaration of Interests: The authors stated: "None." Ethics Approval Statement: All patients provided signed informed consent and the study protocol was approved by the Research Ethics Committee of Nanjing Drum Tower Hospital.