Genomic alterations of cerebrospinal fluid cell-free DNA in leptomeningeal metastases of gastric cancer

Abstract

Background Leptomeningeal metastases (LM) were rare in gastric cancer (GC), and GC patients with LM (GCLM) generally suffer from poor prognosis. Nevertheless, the clinical utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was underinvestigated in GCLM. Methods We retrospectively studied 15 GCLM patients, and all patients had paired primary tumor tissue samples and post-LM CSF samples while 5 patients also had post-LM plasma samples. All samples were analyzed using next-generation sequencing (NGS), and the molecular and clinical features were correlated with clinical outcomes. Results CSF had higher mutation allele frequency (P = 0.015), more somatic mutations (P = 0.032), and more copy-number variations (P < 0.001) than tumor or plasma samples. Multiple genetic alterations and aberrant signal pathways were enriched in post-LM CSF, including CCNE1 amplification and cell cycle-related genes, and CCNE1 amplification was significantly associated with patients’ overall survival (P = 0.0062). More potential LM progression-related markers were detected in CSF samples than in tumor samples, including PREX2 mutation (P = 0.014), IGF1R mutation (P = 0.034), AR mutation (P = 0.038), SMARCB1 deletion (P < 0.001), SMAD4 deletion (P = 0.0034), and TGF-beta pathway aberration (P = 0.0038). Additionally, improvement in intracranial pressure (P < 0.001), improvement in CSF cytology (P = 0.0038), and relatively low levels of CSF ctDNA (P = 0.0098) were significantly associated with better PFS. Lastly, we reported a GCLM case whose CSF ctDNA dynamic changes were well correlated with his clinical assessment. Conclusions CSF ctDNA could more sensitively detect molecular markers and metastasis-related mechanisms than tumor tissues in GCLM patients, and our study sheds light on utilizing CSF ctDNA in prognostic estimation and clinical assessment in GCLM.

Cerebrospinal Fluid Circulating Tumor DNA Genotyping and Survival Analysis in Lung Adenocarcinoma With Leptomeningeal Metastases

“…What's more, we demonstrated that CSF ctDNA has a signifcantly higher detection rate than plasma. This result is consistent with previous study which show that CSF ctDNA exhibite a more comprehensive genetic landscape than plasma of CNS metastases [14,16,17,19]. Previous studies have compared the detection rate of EGFR and found that it is higher in CSF than plasma.…”

Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers

“…Few rare GC cases metastasize in the leptomeningeal region, giving rise to gastric cancer with a leptomeningeal metastasis (GCLM) subtype. Quantifying post-therapy cfDNA in the CSF of such cases provides various prognostic clues, such as this study ( Chen et al, 2023 ), which reported that reduced cfDNA levels in the CSF indicated better PFS in GCLM patients. In such cases, identifying levels and genomic alterations in CSF ctDNA could hold promising potential to provide prognostic decisions and clinical assessment.…”