Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

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Abstract
H3 K27‐altered diffuse midline glioma is a highly lethal pediatric‐type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27‐altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M‐mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M‐mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M‐mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M‐mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53‐mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis 10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M‐mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M‐mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.
Funding Information
  • Beijing Nova Program (Z201100006820118)
  • National Natural Science Foundation of China (81903078, 82172783)

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