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Background This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM).Methods A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were blasted in GenBank and bioinformatically analyzed.Results Cancer-associated gene mutations occurred in all 62 CSF ctDNA samples in TP53 (54/62; 87.10%), EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes enriched by the KEGG pathway analysis were the PI3K-Akt, which included the genes of TP53 , EGFR , PTEN , KIT and KDR. After receiving intrathecal and systemic chemotherapy, the ERK1/2 signaling pathways of these CSF samples were activated. Furthermore, the CNVs of these genes were also identified in these 62 samples.Conclusions This study identified gene mutations in all CSF ctDNA samples, indicating that such an approach could be useful as a second-line diagnostic strategy for NM patients. PI3K-Akt signaling may be the potential NM metastasis mechanism.

Background Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical signs and symptoms, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging (contrast-enhanced brain MRI and/or CT) features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease. Methods A total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF tumor-derived circulating tumor DNA (ctDNA) extraction and cancer-associated gene mutations detection by next-generation sequencing (NGS) at the same time. Results The most frequent primary tumor in this study was lung cancer (26/35, 74.29%), followed by gastric cancer (2/35, 5.71%), breast cancer (2/35, 5.71%), prostatic cancer (1/35, 2.86%), parotid gland carcinoma (1/35, 2.86%) and lymphoma (1/35, 2.86%) while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty-five CSF samples (25/35; 71.43%) were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100%) were revealed having detectable ctDNA in which cancer-associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast-enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 62.86%) were consistent with MC. The sensitivity of the neuroimaging was 88.00% (95% confidence intervals [95% CI], 75.26 to 100) (p=22/25) and 62.86% (95% CI, 46.85 to 78.87) (p=22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71.43% (95% CI, 56.46 to 86.40) (n=25/35) compared to that of CSF ctDNA. Conclusions This study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. The utilizing CSF ctDNA as liquid biopsy technology for the diagnosis of MC based on the detection of cancer-associated gene mutations in ctDNA from CSF offers an alternative and DNA-based test for the diagnosis of MC, especially for cases with persistently negative CSF cytology and/or negative neuroimaging findings.

Background Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical signs and symptoms, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging (contrast-enhanced brain MRI and/or CT) features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease.Methods A total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF tumor-derived circulating tumor DNA (ctDNA) extraction and cancer-associated gene mutations detection by next-generation sequencing (NGS) at the same time.Results The most frequent primary tumor in this study was lung cancer (26/35, 74%), followed by gastric cancer (2/35, 6%), breast cancer (2/35, 6%), prostatic cancer (1/35, 3%), parotid gland carcinoma (1/35, 3%) and lymphoma (1/35, 3%) while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty-five CSF samples (25/35; 71%) were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100%) were revealed having detectable ctDNA in which cancer-associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast-enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 63%) were consistent with MC. The sensitivity of the neuroimaging was 88% (95% confidence intervals [95% CI], 75 to 100) (p=22/25) and 63% (95% CI, 47 to 79) (p=22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71% (95% CI, 56 to 86) (n=25/35) compared to that of CSF ctDNA.Conclusions This study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. We find cancer-associated gene mutations in ctDNA from CSF of patients with MC at 100% of our cohort, and utilizing CSF ctDNA as liquid biopsy technology based on the detection of cancer-associated gene mutations may give additional information to diagnose MC with negative CSF cytology and/or negative neuroimaging findings.