Early diagnosis of leptomeningeal disease in diffuse midline gliomas by
detection of H3F3A K27M mutation in circulating tumor DNA of
cerebrospinal fluid
Abstract
Introduction: Leptomeningeal disease (LMD) in diffuse midline
gliomas can lead to devastating symptoms such as severe pain, urinary
incontinence, and tetraparesis, with limited treatment options. In the
present study, we determined whether the detection of H3F3A
K27M-mutant droplets in cerebrospinal fluid (CSF) circulating tumor DNA
(ctDNA) could serve as a reliable biomarker for the detection of LMD in
diffuse midline gliomas. Methods: Twenty-four CSF samples were
obtained from 21 diffuse midline glioma patients. Histological
confirmation of H3F3A K27M mutation was obtained in 9 (42.8%)
cases. ctDNA was extracted from CSF, and H3F3A K27M-mutant and
wildtype droplets were detected using digital droplet PCR (ddPCR). LMD
was diagnosed by CSF cytology and/or pre- and post-contrast head and
whole spine MR imaging. Results: The number of H3F3A
K27M-mutant droplets (median 7 [range 0-297] vs median 0 [range
0-2]; p <.0001) and variant allele frequency (VAF) (median
50.0% [range 7.5-87.5%] vs median 0.0% [range 0.0-40.0%]; p
<.0001)) were significantly higher in the LMD/early LMD group
compared to no LMD group. In two cases (Case 4 and Case 11) without
clinical evidence of LMD, multiple H3F3A K27M-mutant droplets
were detected in the CSF ctDNA. In those cases, extensive spinal
dissemination was detected 175 and 176 days after the initial liquid
biopsy. One case (Case 15) with high Schlafen11 (SLFN11) expression in
the tumor responded well to treatment for LMD and survived for 532 days
after the diagnosis of LMD. Conclusion: This study provides
evidence that detecting H3F3A K27M-mutant droplets in CSF ctDNA
is diagnostic for LMD and is more sensitive than traditional methods
such as CSF cytology and MR imaging.