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Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma
Authors:Yuki Yamagishi  Nobuyoshi Sasaki  Yoshiko Nakano  Yuko Matushita  Takaki Omura  Saki Shimizu  Kuniaki Saito  Keiichi Kobayashi  Yoshitaka Narita  Akihide Kondo  Yoshiaki Shiokawa  Motoo Nagane  Koichi Ichimura
Institution:1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan;2. Department of Neurosurgery, Kyorin University Facility of Medicine, Mitaka-shi, Tokyo, Japan;3. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

Department of Brain Disease Translational Research, Juntendo University Facility of Medicine, Bunkyo-ku, Tokyo, Japan;4. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan;5. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan;6. Department of Brain Disease Translational Research, Juntendo University Facility of Medicine, Bunkyo-ku, Tokyo, Japan

Abstract:The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non-surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell-free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method.
Keywords:central nervous system lymphoma  cerebrospinal fluid  digital PCR  liquid biopsy  MYD88
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