Back to Search
Start Over
Drivers underpinning the malignant transformation of giant cell tumour of bone
- Source :
- Lyskjær, I 2020, ' Drivers underpinning the malignant transformation of giant cell tumour of bone ', Journal of Pathology . https://doi.org/10.1002/path.5537, Fittall, M W, Lyskjær, I, Ellery, P, Lombard, P, Ijaz, J, Strobl, A C, Oukrif, D, Tarabichi, M, Sill, M, Koelsche, C, Mechtersheimer, G, Demeulemeester, J, Tirabosco, R, Amary, F, Campbell, P J, Pfister, S M, Jones, D T W, Pillay, N, Van Loo, P, Behjati, S & Flanagan, A M 2020, ' Drivers underpinning the malignant transformation of giant cell tumour of bone ', Journal of Pathology, vol. 252, no. 4, pp. 433-440 . https://doi.org/10.1002/path.5537, The Journal of Pathology
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- 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. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. ispartof: JOURNAL OF PATHOLOGY vol:252 issue:4 pages:433-440 ispartof: location:England status: published
- Subjects :
- 0301 basic medicine
sarcoma
cyclin D1
Aneuploidy
Bone Neoplasms
histone
medicine.disease_cause
Polymorphism, Single Nucleotide
bone
Pathology and Forensic Medicine
Malignant transformation
03 medical and health sciences
0302 clinical medicine
medicine
genomics
Humans
Promoter Regions, Genetic
Gene
Epigenomics
Giant Cell Tumor of Bone
Original Paper
Mutation
Whole Genome Sequencing
biology
transformation
Cancer
drivers
Methylation
DNA Methylation
medicine.disease
Original Papers
Cell Transformation, Neoplastic
030104 developmental biology
Histone
Giant cell
030220 oncology & carcinogenesis
DNA methylation
osteoclast
Mutation (genetic algorithm)
osteoblast
biology.protein
Cancer research
methylation
epigenetic
giant cell tumour
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Lyskjær, I 2020, ' Drivers underpinning the malignant transformation of giant cell tumour of bone ', Journal of Pathology . https://doi.org/10.1002/path.5537, Fittall, M W, Lyskjær, I, Ellery, P, Lombard, P, Ijaz, J, Strobl, A C, Oukrif, D, Tarabichi, M, Sill, M, Koelsche, C, Mechtersheimer, G, Demeulemeester, J, Tirabosco, R, Amary, F, Campbell, P J, Pfister, S M, Jones, D T W, Pillay, N, Van Loo, P, Behjati, S & Flanagan, A M 2020, ' Drivers underpinning the malignant transformation of giant cell tumour of bone ', Journal of Pathology, vol. 252, no. 4, pp. 433-440 . https://doi.org/10.1002/path.5537, The Journal of Pathology
- Accession number :
- edsair.doi.dedup.....76f5bc58da105afac77a7ae6f8ebcc33