An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene
Abstract Histone mutations (H3 K27M, H3 G34R/V) are molecular features defining subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises in exceptional cases, these...
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2025-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01899-5 |
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| author | Zita Reisz Rita Pereira Smitha Nevis Alan Mackay Leena Bhaw Yura Grabovska Ross Laxton Valeria Molinari Anna Burford Barnaby Clark Cristina Bleil Bassel Zebian Erika Pace Annette Weiser Fernando Carceller Lynley Marshall Andrew King Istvan Bodi Safa Al-Sarraj Chris Jones Matthew Clarke |
| author_facet | Zita Reisz Rita Pereira Smitha Nevis Alan Mackay Leena Bhaw Yura Grabovska Ross Laxton Valeria Molinari Anna Burford Barnaby Clark Cristina Bleil Bassel Zebian Erika Pace Annette Weiser Fernando Carceller Lynley Marshall Andrew King Istvan Bodi Safa Al-Sarraj Chris Jones Matthew Clarke |
| author_sort | Zita Reisz |
| collection | DOAJ |
| description | Abstract Histone mutations (H3 K27M, H3 G34R/V) are molecular features defining subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises in exceptional cases, these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms; MRI imaging identified a brainstem lesion which was biopsied. Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score = 0.99). Further molecular studies (whole exome, whole genome sequencing) revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of H3C3, FGF11 and PIK3CA somatic variants, and a pathogenic germline NBN variant. The RNAseq profile clustered with H3K27M-mutant tumours. A patient-derived cell culture was established enabling unbiased in vitro drug screening; no selective sensitivities were identified. Chromatin immunoprecipitation assays with sequencing (ChIP-seq; H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy, but progressed and passed away 13 months post-diagnosis. This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, illustrating that the H3.1 K27M mutation demonstrates a dominance over the molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study. |
| format | Article |
| id | doaj-art-b89188a231eb48fa89fbbfc54bf0f9f8 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj-art-b89188a231eb48fa89fbbfc54bf0f9f82025-01-19T12:42:45ZengBMCActa Neuropathologica Communications2051-59602025-01-011311610.1186/s40478-024-01899-5An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) geneZita Reisz0Rita Pereira1Smitha Nevis2Alan Mackay3Leena Bhaw4Yura Grabovska5Ross Laxton6Valeria Molinari7Anna Burford8Barnaby Clark9Cristina Bleil10Bassel Zebian11Erika Pace12Annette Weiser13Fernando Carceller14Lynley Marshall15Andrew King16Istvan Bodi17Safa Al-Sarraj18Chris Jones19Matthew Clarke20Department of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustInstitute of Cancer ResearchDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustInstitute of Cancer ResearchDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustInstitute of Cancer ResearchDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustInstitute of Cancer ResearchInstitute of Cancer ResearchPrecision Medicine, King’s College Hospital NHS Foundation TrustNeurosurgery, King’s College Hospital NHS Foundation TrustNeurosurgery, King’s College Hospital NHS Foundation TrustDepartment of Radiology, The Royal Marsden NHS Foundation TrustDepartment of Paediatric and Teenager & Young Adult Neuro-Oncology, The Royal Marsden Hospital NHS Foundation TrustDepartment of Paediatric and Teenager & Young Adult Neuro-Oncology, The Royal Marsden Hospital NHS Foundation TrustDepartment of Paediatric and Teenager & Young Adult Neuro-Oncology, The Royal Marsden Hospital NHS Foundation TrustDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustDepartment of Clinical Neuropathology, King’s College Hospital NHS Foundation TrustInstitute of Cancer ResearchInstitute of Cancer ResearchAbstract Histone mutations (H3 K27M, H3 G34R/V) are molecular features defining subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises in exceptional cases, these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms; MRI imaging identified a brainstem lesion which was biopsied. Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score = 0.99). Further molecular studies (whole exome, whole genome sequencing) revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of H3C3, FGF11 and PIK3CA somatic variants, and a pathogenic germline NBN variant. The RNAseq profile clustered with H3K27M-mutant tumours. A patient-derived cell culture was established enabling unbiased in vitro drug screening; no selective sensitivities were identified. Chromatin immunoprecipitation assays with sequencing (ChIP-seq; H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy, but progressed and passed away 13 months post-diagnosis. This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, illustrating that the H3.1 K27M mutation demonstrates a dominance over the molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study.https://doi.org/10.1186/s40478-024-01899-5Diffuse midline gliomaHistone-mutantHigh-grade gliomaRare case |
| spellingShingle | Zita Reisz Rita Pereira Smitha Nevis Alan Mackay Leena Bhaw Yura Grabovska Ross Laxton Valeria Molinari Anna Burford Barnaby Clark Cristina Bleil Bassel Zebian Erika Pace Annette Weiser Fernando Carceller Lynley Marshall Andrew King Istvan Bodi Safa Al-Sarraj Chris Jones Matthew Clarke An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene Acta Neuropathologica Communications Diffuse midline glioma Histone-mutant High-grade glioma Rare case |
| title | An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene |
| title_full | An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene |
| title_fullStr | An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene |
| title_full_unstemmed | An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene |
| title_short | An exceptionally rare case of a diffuse midline glioma with concomitant H3.1 K27M and G34R mutations in the HIST1H3C (H3C3) gene |
| title_sort | exceptionally rare case of a diffuse midline glioma with concomitant h3 1 k27m and g34r mutations in the hist1h3c h3c3 gene |
| topic | Diffuse midline glioma Histone-mutant High-grade glioma Rare case |
| url | https://doi.org/10.1186/s40478-024-01899-5 |
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