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Early diagnosis of leptomeningeal disease in diffuse midline gliomas by detection of H3F3A K27M mutation in circulating tumor DNA of cerebrospinal fluid
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  • Satoshi Shibuma,
  • Jotaro On,
  • Manabu Natsumeda,
  • Haruhiko Takahashi,
  • Jun Watanabe,
  • Masaki Mitobe,
  • Yuki Tanaka,
  • Yoshihiro Tsukamoto,
  • Masayasu Okada,
  • Junichi Yoshimura,
  • Mari Tada,
  • Hiroshi Shimizu,
  • Junko Murai,
  • Hiroyuki Kawashima,
  • Akiyoshi Kakita,
  • Makoto Oishi
Satoshi Shibuma
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Jotaro On
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Manabu Natsumeda
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka

Corresponding Author:[email protected]

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Haruhiko Takahashi
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Jun Watanabe
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Masaki Mitobe
Niigata Daigaku Igakubu Igakuka Daigakuin Ishigaku Sogo Kenkyuka Ketsueki Naibunpi Taisha Naikagaku Bunya
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Yuki Tanaka
Niigata Daigaku No Kenkyujo
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Yoshihiro Tsukamoto
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Masayasu Okada
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Junichi Yoshimura
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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Mari Tada
Niigata Daigaku No Kenkyujo
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Hiroshi Shimizu
Niigata Daigaku No Kenkyujo
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Junko Murai
Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu
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Hiroyuki Kawashima
Niigata Daigaku Igakubu Igakuka Daigakuin Ishigaku Sogo Kenkyuka
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Akiyoshi Kakita
Niigata Daigaku No Kenkyujo
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Makoto Oishi
Niigata Daigaku No Kenkyujo Rinsho Shinkei Kagaku Bumon Noshinkei Geka
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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.
05 Oct 2024Submission Checks Completed
05 Oct 2024Assigned to Editor
05 Oct 2024Submitted to Pediatric Blood & Cancer
07 Oct 2024Review(s) Completed, Editorial Evaluation Pending
07 Oct 2024Reviewer(s) Assigned
21 Oct 2024Editorial Decision: Revise Major