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

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 <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>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.Rui-Chao Chai and Hao Yan contributed equally to this study.

Clinical Characteristics and Prognostic Factors in H3 K27- altered Diffuse Midline Gliomas: A 64 Cases Retrospective Cohort Analysis

“…Most tumors were located in the thalamus (53.12%). This observation aligns with existing literature emphasizing the diversity of diffuse midline gliomas across various locations and age groups [23][24][25]. Therefore, we conducted a more detailed analysis of both clinical and molecular characteristics across distinct subgroups, considering age and tumor location.…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“… 184 , 185 K27M mutation was found in 30% of children with high‐grade GBM, which was related to adverse clinical outcomes. 186 , 187 The decrease of H3K4me3 content in the promoter was also detected. 188 Christina et al.…”

“…184,185 K27M mutation was found in 30% of children with high-grade GBM, which was related to adverse clinical outcomes. 186,187 The decrease of H3K4me3 content in the promoter was also detected. 188 Christina et al found that the changes in gene expression of various methyltransferases, acetyltransferases, and deacetylases promoted the pathogenesis of GBM.…”

“…Its prognosis is usually unsatisfactory even after appropriate surgical resection, radiotherapy, or chemotherapy 184,185 . K27M mutation was found in 30% of children with high‐grade GBM, which was related to adverse clinical outcomes 186,187 . The decrease of H3K4me3 content in the promoter was also detected 188 .…”

Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance

“…Cancer has become the leading cause of death in China 1 . Gliomas are the most common primary brain tumor and are characterized by rapid malignant progression, poor response to radiotherapy and chemotherapy, high recurrence and mortality rates, and a poor prognosis [2][3][4][5][6] . Currently, the firstline orphan chemotherapy drug for glioma clinical treatment is temozolomide (TMZ), but some patients are not responsive to TMZ and responsive patients may develop drug resistance after treatment, thus limiting the clinical efficacy of TMZ 7,8 .…”