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

Peng Wang; Henghui Zhang; Peng Chen; Zengfeng Sun; Zhen Zhang; Qiang Yin; Huaibo Sun; Jinpu Yu

doi:10.2147/CMAR.S295368

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

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

Authors

Peng Wang^#^{1

2}, Henghui Zhang³, Peng Chen³, Zengfeng Sun^{1

2}, Zhen Zhang^{1

2}, Qiang Yin^{1

2}, Huaibo Sun³, Jinpu Yu^#^{2

4}

Affiliations

¹ Department of Neuro-Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
² Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, People's Republic of China.
³ Genecast Biotechnology Co., Ltd, Wuxi, 214000, People's Republic of China.
⁴ Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.

^# Contributed equally.

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.

Grants and funding

This work was supported by National Science and Technology Major Project (Grant No. 2018ZX09201-015), Project of Science and Technology of Tianjin (Grant No. 18JCQNJC82700), and Key Project of Tianjin Health and Family Planning Commission (Grant No.16KG126).