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Genetic alteration analysis of non-pediatric diffuse midline glioma, H3 K27-altered
Hanbin Jang1, Seyoung Moon1, Hyun Jung Kwon2
1Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea.
Abstract:
Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥ 3) were observed in 11 (61.1%) patients. H3F3A (H3 K27 M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes.
Insights
Diffuse midline gliomas with H3 K27-alteration (DMGH3) in adults show better survival than in children. TP53 mutations correlate with high-grade tumors and worse outcomes, while FGFR1/PIK3CA mutations offer potential therapeutic targets.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Genetics
Background:
- Diffuse midline gliomas with H3 K27-alteration (DMGH3) are aggressive brain tumors, predominantly affecting pediatric populations but also occurring in adults.
- Understanding the genetic landscape and clinicopathological features of adult DMGH3 is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the clinicopathological significance of genetic alterations in non-pediatric DMGH3.
- To identify potential targetable genetic mutations for personalized treatment strategies in adult DMGH3 patients.
Main Methods:
- Next-generation sequencing (NGS) was performed on tumor samples from 18 non-pediatric DMGH3 patients.
- Immunohistochemistry and NGS were used to identify H3F3A (H3 K27M) alterations.
- Clinicopathological data and overall survival (OS) were analyzed in correlation with genetic findings.
Main Results:
- All 18 patients had H3F3A (H3 K27M) alterations. TP53 mutations were identified in 61.1% of cases.
- TP53 mutations significantly correlated with high-grade histology (WHO grade ≥ 3) and poorer overall survival (OS).
- Targetable mutations in FGFR1 or PIK3CA were found in 16.7% of patients, while ATRX, NF1, KRAS, and ATM alterations were also observed.
Conclusions:
- Non-pediatric DMGH3 predominantly occurs in the thalamus-hypothalamus and exhibits a better prognosis than pediatric cases.
- TP53 alterations are associated with high-grade histology and reduced survival in this cohort.
- The presence of targetable mutations like FGFR1 and PIK3CA highlights the potential for personalized medicine approaches in adult DMGH3.
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