K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway

Joyon, Natacha; Tauziède‐Espariat, Arnault; Alentorn, Agustí; Giry, Marine; Castel, David; Laurent, Césari; Zanello, Marc; Varlet, Pascale; Bielle, Franck

doi:10.1111/nan.12329

Cited by 52 publications

(35 citation statements)

References 12 publications

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“…Positive staining for glial and neuronal components was clearly observed by IHC (Figure A–F). In one case [described by Joyon et al ], the BRAF V600E mutation was detected at diagnosis but lost at spontaneous malignant transformation, as shown by IHC and confirmed by sequencing. In this peculiar case, no BRAF V600E positive clone was detected by IHC and no CMMRD was found by IHC.…”

Section: Resultsmentioning

confidence: 99%

“…Sections for genetic analyses and IHC were prepared from zinc formalin‐fixed paraffin‐embedded tissue specimens (5% formalin, 3 g/L zinc, 8 g/L sodium chloride) or frozen tissues. Two cases displaying anaplastic transformation were described in previous studies .…”

Section: Methodsmentioning

confidence: 99%

“…However, rare cases of H3 K27M mutant grade I GG and pilocytic astrocytomas were recently described, suggesting that H3 K27M mutations may be present in a spectrum of glial tumors. H3 K27M mutations should not be used as the sole criterion for the diagnosis of WHO Grade IV midline gliomas (19,29). In one of these cases, the H3 K27M mutation was associated with a BRAF V600E mutation.…”

Section: Introductionmentioning

confidence: 99%

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Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

Pagès

Beccaria²,

Boddaert³

et al. 2017

Brain Pathology

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Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As cooccurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

Pagès

Beccaria²,

Boddaert³

et al. 2017

Brain Pathology

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“…In spite of the WHO 2016 update grading, some recent studies found that diffuse midline glioma H3K27M has more variety in its histomorphology, i.e., features of WHO grades I–IV, and that the prognosis of the patients is not always poor [16-19]. In this study, we focused on the H3K27M mutation immunopositive tumors.…”

Section: Introductionmentioning

confidence: 99%

Immunostaining of Increased Expression of Enhancer of Zeste Homolog 2 (EZH2) in Diffuse Midline Glioma H3K27M-Mutant Patients with Poor Survival

et al. 2019

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Introduction: The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, this interaction leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation-positive tumors and revealed the association of high EZH2 expression with poor survival. Methods: Our study included 12 patients, with an age range of 6–56 years and treated between 2007 and 2016. All patients underwent MRI study for nonenhanced T1, T2, diffusion, gadolinium-enhanced T1-weighted imaging, and fluid-attenuated inversion recovery (FLAIR). Immunohistochemical staining was performed against H3K27M, H3K27me3, EZH2, EED, mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, O6-methylguanine-DNA methyltransferase (MGMT), and Ki-67 antibodies. Results: All patients were negative for IDH1R132H and H3K27me3, but H3K27M-positive. Staining against EZH2 was negative in all histological features of grade II cases (3/12) and positive in grade III and IV cases; EZH2 positivity is associated with poor prognosis (p = 0.0082). EZH2 positivity was not associated with EED positivity. Retained ATRX staining was found mostly in grade III and IV cases (6/12). P53 was predominantly positive in cases of astrocytoma and glioblastoma (8/12). The labeling index of Ki-67 was 1.2–31.4% for grade II and III histological features and 11.2–24.8% for grade IV. Conclusion: We suggest that the expression of EZH2 is not associated with the PRC2 pathway and increases in patients with H3K27M-mutant diffuse midline glioma and a poor prognosis. Further studies are necessary to understand the mechanism involved.

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“…Except for the lack of pathological features such as an infiltrative nature and astrocytic differentiation, the remaining characteristics of the patient (i.e., age, tumor location, and genetic profile) fulfill the diagnostic criteria of "diffuse midline glioma, H3 K27M-mutant (DMG-K27M mutant)," according to the WHO 2016 classification. 15 Moreover, an analysis of 54 pediatric patients with grade I GG revealed that five subjects (9.3%) presented with H3F3A K27M mutations; all also carried the BRAF V600E mutant tumors. [9][10][11][12][13] This tumor entity is categorized as WHO grade IV based on its dismal prognosis.…”

Section: Discussionmentioning

confidence: 99%

Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord

et al. 2018

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The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced "diffuse midline glioma H3 K27M mutant" as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10-year-old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations.

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K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway

Cited by 52 publications

References 12 publications

Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

Immunostaining of Increased Expression of Enhancer of Zeste Homolog 2 (EZH2) in Diffuse Midline Glioma H3K27M-Mutant Patients with Poor Survival

Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord

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