METB-07. MINIMALLY-INVASIVE DIAGNOSIS OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) USING CEREBROSPINAL FLUID CELL-FREE DNA SEQUENCING IN PEDIATRIC AND YOUNG ADULT PATIENTS

Abstract

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) presents with nodular leptomeningeal disease throughout the neuroaxis. Histology shows variable presence of a low density intraparenchymal lesion containing OLIG2-expressing neoplastic cells. Molecularly, DLGNT is characterized by the presence of KIAA1549::BRAF fusion and chromosome arm 1p deletion. Concomitant gain of chromosome arm 1q is associated with poor prognosis. Diagnosis by meningeal biopsy is often non-diagnostic and we hypothesized analysis of cell free DNA (cfDNA) from cerebrospinal fluid (CSF) could represent a superior diagnostic modality. We analyzed CSF samples from 7 patients, median age of 18 years, with DLGNT including matched germline DNA. MSK-IMPACT, a hybridization capture-based next-generation DNA sequencing panel, was utilized to analyze the DNA. Prior tissue biopsy was done in 5/7 patients. Of these, biopsy was non-diagnostic in 3 patients and positive for the KIAA1549:BRAF fusion in 2. Analysis of CSF cfDNA detected KIAA1549::BRAF fusion in 5/7 (71%) of patients, including all patients with prior non-diagnostic biopsy or tissue quantity insufficient for molecular testing. Analysis of CSF cfDNA copy number profiles revealed 1p-/1q+ in 6 patients and 1p- only in the remaining 1 patient, fully concordant with available prior tissue testing in all instances. In 2 patients with prior tissue-confirmed KIAA1549::BRAF fusion, the fusion was not detected in CSF cfDNA during/after treatment with a MEK inhibitor, but additional somatic alterations and DNA copy number profiles were similar to the prior biopsies. Additional somatic alterations were identified in ATRX, BCOR, RARA, STAT5A, SPOP, PPM1D, MED12, KMT2C, RECQL and SETD2, including likely oncogenic secondary driver alterations that have not been previously reported in DLGNT. Given the high molecular diagnostic yield and concordance with open biopsy, cfDNA CSF sequencing should be considered as a first line diagnostic maneuver for patients with MRI findings suspicious for DLGNT, followed by open biopsy only if CSF is non-diagnostic.