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. 2021 Jun 21:13:4853-4863.
doi: 10.2147/CMAR.S295368. eCollection 2021.

The Presence of Genomic Instability in Cerebrospinal Fluid in Patients with Meningeal Metastasis

Peng Wang #  1   2 , Henghui Zhang  3 , Peng Chen  3 , Zengfeng Sun  1   2 , Zhen Zhang  1   2 , Qiang Yin  1   2 , Huaibo Sun  3 , Jinpu Yu #  2   4
Affiliations

The Presence of Genomic Instability in Cerebrospinal Fluid in Patients with Meningeal Metastasis

Peng Wang et al. Cancer Manag Res. .

Abstract

Purpose: This study aimed to explore the genomic instability in cerebrospinal fluid (CSF) in patients with meningeal metastasis (MM).

Material and methods: We collected the blood and CSF samples of 15 MM patients and one brain parenchymal metastasis (BPM) patient. A panel of 543 cancer-related genes was conducted to analyze the status of genomic instability in CSF and plasma cell-free DNA (cfDNA) of all patients. Subsequently, nine patients underwent low-depth whole-genome sequencing (WGS) analysis to verify the existence of genomic instability, followed by genomic scoring by the application of aneuploidy scores. Diagnosis-specific graded prognostic assessment (DS-GPA) score was utilized to assess the clinical status of MM patients.

Results: There was significant difference in gene mutation between CSF cfDNA and plasma cfDNA in MM patients. Among them, 12 MM patients developed genomic instability in their CSF cfDNA, while the remaining 3 had stable genetic profile. Besides, BPM patients showed genomic stability in his CSF and paraffin-embedded tissue sections. No genomic instability was noticed in plasma cfDNA of all patients. Sensitive mutations on EGFR, ERBB2, ALK and KRAS genes and increased gene copy numbers of MET and ERBB2 were detected in 10 MM patients with genomic instability, as well as the EGFR gene mutation in one MM case with genomic stability. Additionally, MM patients with genomic instability had lower overall survival and higher aneuploidy scores and tumor mutation burden compared with those with genomic stability. Moreover, MM patients with higher DS-GPA scores benefited from better survival.

Conclusion: Genomic instability existed in the CSF cfDNA rather than plasma cfDNA of MM patients, which might be the underlying cause of the differences in MM.

Keywords: cell-free DNA; cerebrospinal fluid; genomic instability; meningeal metastasis; panel; whole-genome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
The blood and cerebrospinal fluid of 15 meningeal metastasis patients and 1 brain parenchymal metastasis patient were detected by a panel of 543 cancer-related genes. Heatmap displayed gene mutations in CSF and blood of these patients.
Figure 2
Figure 2
(A–L) A panel analysis of 543 cancer-related genes in blood and CSF in 12 patients with genomic instability. (M–O) A panel analysis of 543 cancer-related genes in blood and CSF in three patients with genomic stability. (P) A panel analysis of 543 cancer-related genes in blood and CSF in a brain parenchymal metastasis patient.
Figure 3
Figure 3
(A–F) Copy number variation in blood and CSF in six meningeal metastasis patients with genomic instability. The log2 ratio value is plotted on the y-axis; the x-axis represents chromosomes. Red indicates copy number gain, green indicates copy number loss, and blue indicates no change.
Figure 4
Figure 4
(A and B) Copy number variation in blood and CSF in two meningeal metastasis patients with genomic stability. (C) Copy number variation in blood and CSF in brain parenchymal metastasis case with genomic stability. The log2 ratio value is plotted on the y-axis; the x-axis represents chromosomes. Red indicates copy number gain, green indicates copy number loss, and blue indicates no change.
Figure 5
Figure 5
Overall survival analysis between meningeal metastasis patients with genomic instability and genomic stability.
See this image and copyright information in PMC

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