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

Abstract

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 cellfree 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.

Sequencing of cerebrospinal fluid in non‐small‐cell lung cancer patients with leptomeningeal metastasis: A systematic review

“…Aneuploidy, another trigger of genomic instability, is also widely detected in patients in CSF from LM patients. 42 The coexistence of genomic instability and aneuploidy could promote each other and lock in a vicious cycle, leading to genomic copy number changes. The CNVs facilitate tumor cells to acquire phenotypes to survive under selective pressure such as anti‐cancer therapy.…”

“…TP53 LOH uniquely occurred in CSF rather than plasma, accompanied by more genomic mutations and CNVs. Aneuploidy, another trigger of genomic instability, is also widely detected in patients in CSF from LM patients 42 . The coexistence of genomic instability and aneuploidy could promote each other and lock in a vicious cycle, leading to genomic copy number changes.…”

Genomic Instability in Cerebrospinal Fluid Cell-Free DNA Predicts Poor Prognosis in Solid Tumor Patients with Meningeal Metastasis

“…However, until our study last year, few studies specifically examining GI in patients with MM had been conducted [ 14 ]. Normally, the GI status is analyzed using genomic DNA samples from tumor tissues rather than cell-free circulating tumor DNA (ctDNA) extracted from plasma, though, in many cases, cfDNA has been used as a surrogate reflecting the genomic profile of solid tumors for concomitant diagnosis, minimal residual disease (MRD) surveillance, and the identification of drug resistance mechanisms [ 15 , 16 , 17 ].…”

“…CSF is a circulating fluid unique to the central nervous system, filling the ventricles and spinal cord, that comes into direct contact with tumor cells at intracranial lesions and is expected to be a breakthrough point for the liquid biopsy of brain tumors [ 18 , 19 , 20 ]. In our previous study, we found that the GI status in the MM of multiple solid tumors could be analyzed using CSF cfDNA [ 14 ]. In the present study, we established a GI score relying on high-throughput genetic testing to describe the GI status in CSF cfDNA and assess its clinical significance as a prognostic indicator in solid tumor patients with MM.…”