Journal of neuro-oncology · 2026
Early experience with cerebrospinal fluid cell-free DNA molecular profiling in a neuro-oncology practice.
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Riviere-Cazaux Cecile, Kumar Rahul, Rechberger Julian S, Obiri-Yeboah Derrick, Dai Chao, Li Jie, Huang Yong, Warrington Arthur E, Sharif Essa H, Palmer Elizabeth A, Wang Xiaohong, Lachance Daniel H, Kizilbash Sani H, Ruff Michael W, Carabenciov Ivan D, Fortin Ensign Shannon P, Zadeh Gelareh, Neth Bryan J, Sener Ugur, Du Pan, Jia Shidong, Burns Terry C
Аннотация
PURPOSE: Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) is increasingly used as a liquid biopsy in neuro-oncology for diagnosing lesions of uncertain etiology, distinguishing progression from pseudoprogression, and ruling out leptomeningeal disease (LMD). We assessed our institution's early experience with a new CSF cfDNA molecular profiling assay for detecting variant alleles (VA) and copy-number alterations (CNA) across these indications in our neuro-oncology practice.
METHODS: Beginning in August 2021, providers could request research CSF cfDNA sequencing from clinically indicated lumbar punctures. Following extraction, targeted next-generation sequencing (NGS) and/or low-pass whole-genome sequencing (LPWGS) were performed. VAs and CNAs were summarized by indication and integrated with clinical features, cfDNA yield, matched tissue data, and overall survival.
RESULTS: CSF samples from seventy-six consecutive patients were analyzed and retrospectively classified into three categories: lesions of uncertain etiology (46%), question of CNS progression (21%), or ruling out LMD (26%). Median cfDNA yield was 0.27 ng/mL (IQR = 0.05-0.61 ng/mL). VA and/or CNA detection, hereafter designated "tumor calls," were identified in 20 patients (26%), with 29 patients having negative tumor calls (38%) and 27 patients (36%) having insufficient cfDNA yield/quality. A copy number burden threshold of 7.42 accurately identified tumor-specific CNAs (AUC 0.998) and was associated with poorer survival (HR 3.4, p = 0.006). Overall survival for patients with positive tumor calls was significantly lower than for patients with negative tumor calls or low yield (p = 0.003).
CONCLUSION: Despite low cfDNA abundance, CSF NGS and LPWGS provide informative data across neuro-oncologic indications. Further work is underway to optimize the assays for low input CSF cfDNA.
METHODS: Beginning in August 2021, providers could request research CSF cfDNA sequencing from clinically indicated lumbar punctures. Following extraction, targeted next-generation sequencing (NGS) and/or low-pass whole-genome sequencing (LPWGS) were performed. VAs and CNAs were summarized by indication and integrated with clinical features, cfDNA yield, matched tissue data, and overall survival.
RESULTS: CSF samples from seventy-six consecutive patients were analyzed and retrospectively classified into three categories: lesions of uncertain etiology (46%), question of CNS progression (21%), or ruling out LMD (26%). Median cfDNA yield was 0.27 ng/mL (IQR = 0.05-0.61 ng/mL). VA and/or CNA detection, hereafter designated "tumor calls," were identified in 20 patients (26%), with 29 patients having negative tumor calls (38%) and 27 patients (36%) having insufficient cfDNA yield/quality. A copy number burden threshold of 7.42 accurately identified tumor-specific CNAs (AUC 0.998) and was associated with poorer survival (HR 3.4, p = 0.006). Overall survival for patients with positive tumor calls was significantly lower than for patients with negative tumor calls or low yield (p = 0.003).
CONCLUSION: Despite low cfDNA abundance, CSF NGS and LPWGS provide informative data across neuro-oncologic indications. Further work is underway to optimize the assays for low input CSF cfDNA.