Histone H3 K27M mutations in adult cerebellar high-grade gliomas

Nakata, Satoshi; Nobusawa, Sumihito; Yamazaki, Tatsuya; Osawa, Tadashi; Horiguchi, Keishi; Hashiba, Yasuhiro; Yaoita, H.; Matsumura, Nozomi; Ikota, Hayato; Hirato, Junko; Yoshimoto, Yuhei; Yokoo, Hideaki

doi:10.1007/s10014-017-0288-6

Cited by 26 publications

(24 citation statements)

References 30 publications

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“…[1][2][3][4]12 Because of its rarity, the nature of the cerebel- no tumors with an IDH1/2 mutation. 8 Nakata et al also detected two H3F3A K27M mutated tumors among 10 cerebellar high-grade glioma cases, 11 in which our two IDHmutated tumors were included. In diffuse glioma, the IDH status is essential for integrated diagnosis by the WHO classification system (2016).…”

Section: Discussionmentioning

confidence: 99%

“…These tumor cells resembled epithelioid or rhabdoid cells. Tumor cells were also positive for IDH1 R132H (H09, monoclonal, 1:50; Dianova, Hamburg, Germany) ( 10,11 and revealed an IDH1 c.G395A (R132H) mutation (Fig. 2B) or features of high-grade astrocytoma such as oval nuclei and eosinophilic cytoplasm with processes.…”

Section: Casementioning

confidence: 99%

“…Tumor cells were also positive for IDH1 R132H (H09, monoclonal, 1:50; Dianova, Hamburg, Germany) ( Fig. 2E), but negative for p53 (monoclonal, 1:50; Leica Microsystems, Wetzlar, Germany), BRAF V600E (VE1, 10,11 and revealed an IDH1 c.G395A (R132H) mutation (Fig. 2F), whereas IDH2, H3F3A and BRAF were intact.…”

Section: Casementioning

confidence: 99%

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Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

et al. 2018

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Cerebellar high-grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH-mutated cerebellar high-grade glioma with unusual histological features and uncommon patient ages. One case was an 83-year-old man, whose tumor was predominantly composed of densely packed round-to-polygonal epithelioid cells. The other was a 75-year-old woman's high-grade astrocytoma characterized by cord-like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH-mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2-mutation. Although the number is limited, IDH-mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.

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Section: Discussionmentioning

confidence: 99%

Section: Casementioning

confidence: 99%

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Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

et al. 2018

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“…Curative surgery is not possible, radiation therapy provides only temporary relief, and chemotherapies have thus far proven wholly ineffective (2,3). The current World Health Organization (WHO) diagnostic classification of diffuse midline glioma (DMG) is now categorically defined by the presence of the H3K27M mutation (4), and the clinical relevance ascribed to this genetic lesion highlights its unifying role as the biologic driver across a range of midline glial tumors involving the thalamus, cerebellum, brainstem (DIPG), and spinal cord (5)(6)(7). The presence of the H3K27M mutation in these tumors conveys a uniformly dismal prognosis regardless of tumor location or histologic grade (6,8).…”

Section: Introductionmentioning

confidence: 99%

Super elongation complex as a targetable dependency in diffuse midline glioma

Dahl

Danis

Balakrishnan

et al. 2020

Preprint

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AbstractMutations in the histone 3 gene (H3K27M) are the eponymous drivers in diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. The salient molecular consequence of these recurrent oncohistones is a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify specific, therapeutically targetable epigenetic dependencies within this disease context, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cultures. This approach identified AFF4, the scaffold protein of the super elongation complex (SEC), as a previously-undescribed dependency in DMG. Interrogation of SEC function demonstrated a key role for maintaining DMG cell viability and clonogenic potential while promoting self-renewal of DMG tumor stem cells. Small-molecule inhibition of the SEC with the highly-specific, clinically relevant CDK9 inhibitors atuveciclib and AZD4573 restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a biologic rationale for translational exploration of CDK9 inhibition as a promising therapeutic approach in a disease which currently has no effective medical therapies.

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“…Extracted DNA of the two components was amplified by polymerase chain reaction and then sequenced with primers for IDH1/2, TP53, TERT promoter and BRAF as described elsewhere . DNA sequencing demonstrated that each component harbored IDH1 G395A mutation and TERT promoter C228T mutation (Fig.…”

Section: Pathological Findingsmentioning

confidence: 99%

Oligodendroglioma showing pleomorphic xanthoastrocytoma‐like perivascular microlesion: With IDH1, TERT promoter mutation and 1p/19q codeletion detected in both components

Murakami

Ikota

Nobusawa

et al. 2019

Pathology International

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We report a histological and genetic study of concurrent oligodendroglioma and a microscopic pleomorphic xanthoastrocytoma (PXA)-like lesion in a 48-year-old male. He presented with generalized seizure, and magnetic resonance imaging revealed a nonenhanced left frontal lobe mass suggesting low-grade glioma. The patient underwent craniotomy and tumor resection. Histopathological examination of the surgical specimen showed an oligodendroglioma with a PXA-like element; the latter measured 0.9 mm and occupied a Virchow-Robin space of the superficial cortex. The whole tumor had no elevated mitotic activity, microvascular proliferation or necrosis. Each component was immunohistochemically isocitrate dehydrogenase (IDH1)-R132H positive, p53 negative and ATRX positive. Genetic analyses clarified identical IDH1 G395A mutation, promoter C228T mutation and 1p/19q codeletion in both elements. Careful integration of histology and telomerase reverse transcriptase (TERT) molecular parameters revealed that this case was an oligodendroglioma showing PXA-like features, rather than a collision tumor. This case provides further insights into the gliomagenesis. K E Y W O R D S 1p/19q-codeletion, IDH, oligodendroglioma, pleomorphic xanthoastrocytoma

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Histone H3 K27M mutations in adult cerebellar high-grade gliomas

Cited by 26 publications

References 30 publications

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

Super elongation complex as a targetable dependency in diffuse midline glioma

Oligodendroglioma showing pleomorphic xanthoastrocytoma‐like perivascular microlesion: With IDH1, TERT promoter mutation and 1p/19q codeletion detected in both components

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