Abstract
BackgroundCentral nervous system lymphomas (CNSL) is a devastating disease. Currently, a confirmatory biopsy is required prior to treatment.ObjectiveOur investigation aims to prove the feasibility of a minimally-invasive diagnostic approach for the molecular characterization of CNSL.MethodsTissue biopsies from 6 patients with suspected CNSL were analyzed using a 649gene next-generation sequencing (NGS) tumor panel (tumor vs. reference tissue (EDTA-blood)). The individual somatic mutation pattern was used as a basis for the digital PCR analyzing circulating tumor DNA (ctDNA) from plasma and cerebrospinal fluid (CSF) samples, identifying one selected tumor mutation during this first step of the feasibility investigation.ResultsNGS-analysis of biopsy tissue revealed a specific somatic mutation pattern in all confirmed lymphoma samples (n = 5, NGS-sensitivity 100%) and none in the sample identified as normal brain tissue (NGS-specificity 100%). cfDNA-extraction was dependent on the extraction-kit used and feasible in 3 samples, in all of which somatic mutations were detectable (100%). Analysis of CSF-derived cfDNA was superior to plasma-derived cfDNA and routine microscopic analysis (lymphoma cells: n = 2, 40%). One patient showed a divergent molecular pattern, typical of Burkitt-Lymphoma (HIV+, serologic evidence of EBV-infection). Lumbar puncture was tolerated without complications, whereas biopsy caused 3 hemorrhages.ConclusionsOur investigation provides evidence that analysis of cfDNA in central nervous system tumors is feasible using the described protocol. Molecular characterization of CNSL could be achieved by analysis of CSF-derived cfDNA. Knowledge of a tumor’s specific mutation pattern may allow initiation of targeted therapies, treatment surveillance and could lead to minimally-invasive diagnostics in the future.
Highlights
Central nervous system lymphomas (CNSL) is a devastating disease
Molecular characterization of CNSL could be achieved by analysis of CSFderived circulating free DNA (cfDNA)
We investigated the feasibility of molecular characterization of CNSL based on tissue samples applying next-generation sequencing (NGS) and detection of specific mutations in the periphery analyzing circulating tumor DNA (ctDNA) from plasma and cerebrospinal fluid (CSF), which could aid in treatment surveillance and compilation of personalized treatment plans
Summary
Central nervous system lymphomas (CNSL) is a devastating disease. A confirmatory biopsy is required prior to treatment. Central nervous system lymphoma (CNSL) is a rare entity among intracranial neoplasms, comprising only 4% of all intracranial tumors [1]. Needle biopsy remains the gold standard with a diagnostic accuracy of 73–97% and a considerable procedural morbidity (≤16.1%) and mortality (≤3.9%), requiring re-operations in selected cases [3]. Several molecular markers and circulating proteins have been identified using peripheral blood samples [10,11,12]. The plasma may not be optimal for detection of ctDNA from CNS-tumors due to the blood brain barrier [10, 13]
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