Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone

Yamamoto, Hidetaka; Iwasaki, Takeshi; Yamada, Yuichi; Matsumoto, Yoshihiro; Otsuka, Hiroshi; Yoshimoto, Masami; Kohashi, Kenichi; Taguchi, Kenichi; Yokoyama, Ryohei; Nakashima, Yasuharu; Oda, Yoshinao

doi:10.1016/j.humpath.2017.11.020

Cited by 81 publications

(80 citation statements)

References 26 publications

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“…In the current study, the treatment of patients with GCT of bone with denosumab, chemotherapy, or radiotherapy did not appear to alter the intensity or extent of H3G34W staining, in keeping with the findings reported in a very recent study by Yamamoto et al 22 In contrast, Luke et al reported a reduction in the H3G34W-positive cells in GCT of bone after treatment with denosumab. 25 At the molecular level, conflicting results also have been reported.…”

Section: Discussionsupporting

confidence: 91%

“…Therefore, in tumors with an otherwise classic morphology and clinical presentation, negative H3G34W staining should not exclude a diagnosis of GCT of bone. Sequencing analysis and/or additional IHC with variant mutant‐specific antibodies may aid in confirming the diagnosis, if necessary …”

Section: Discussionmentioning

confidence: 99%

“…Sequencing analysis and/or additional IHC with variant mutant-specific antibodies may aid in confirming the diagnosis, if necessary. 22 The reported frequency of H3F3A mutations in GCT of bone appears to depend on the sequencing approaches, and ranges from 69% for Sanger sequencing 13 to 96% for targeted massively parallel sequencing. 16 With a detection rate of approximately 15% to 20% mutant alleles, 23 Sanger sequencing may not always be sensitive enough and previously was shown to miss an H3F3A mutation at a mutant allele fraction of 12%, which was detected by pyrosequencing.…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy

Schaefer

Fletcher

Nielsen

et al. 2018

Cancer Cytopathology

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy

Schaefer

Fletcher

Nielsen

et al. 2018

Cancer Cytopathology

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“…IHC expression of G34W is more specific, sensitive and valuable for differential diagnosis from other histologically ambiguous giant cell-rich lesions including chondroblastoma, malignant giant cell-rich osteosarcoma and aneurysmal bone cyst. Even in metastatic, recurrent, secondary malignant and post-denosumab GCTBs, H3F3A G34W mutation and its IHC expression are maintained ( 32 ). Knockdown of this mutation counteracts the neoplastic phenotype, implying that H3F3A-G34W is sufficient to drive tumorigenesis of GCTB ( 33 ).…”

Section: Histopathology and Genetics Of Gctbmentioning

confidence: 99%

“…Under physiological conditions, it is osteoclasts that induce osteoblastic bone formation by various growth factors including TGF-β and IGF-1 in the context of bone remodeling ( 73 ). In GCTB, however, the osteoclasts probably suppress the osteogenic differentiation of stromal cells via various mediating factors ( 32 , 74 ). After denosumab therapy, both osteoclast maturation from precursors and function are blocked due to the inhibition of RANK/RANKL axis.…”

Section: Morphological Immunohitochemical and Molecular Changes Of Gmentioning

confidence: 99%

Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls

Gao

et al. 2020

Front. Oncol.

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Denosumab is a monoclonal antibody against RANK ligand for treatment of giant cell tumor of bone (GCTB). Clinical trials and case series have demonstrated that denosumab is relevant to beneficial tumor response and surgical down-staging in patients of GCTB. However, these trials or case series have limitations with a short follow-up. Recent increasing studies revealed that denosumab probably increased the local recurrence risk in patients treated with curettage. This may be caused by the thicken bone margin of tumor that trapped tumor cells from curettage. The direct bone formation by tumor cells in the margin after denosumab treatment also contributed to the local recurrence. in vitro studies showed denosumab resulted in a cytostatic instead of a true cytotoxic response on neoplastic stromal cells. More importantly, denosumab-treated GCTB exhibited morphologic overlap with malignancy, and a growing number of patients of malignant transformation of GCTB during denosumab treatment have been reported. The optimal duration, long term safety, maintenance dose, and optimum indications remain to be elucidated. With these concerns in mind, this review warns that the denosumab therapy of GCTB should be applied with caution.

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Drivers underpinning the malignant transformation of giant cell tumour of bone

Fittall

Lyskjær

Ellery

et al. 2020

The Journal of Pathology

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The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases.

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Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone

Cited by 81 publications

References 26 publications

Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy

Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy

Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls

Drivers underpinning the malignant transformation of giant cell tumour of bone

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