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@ARTICLE{Fittall:157748,
      author       = {M. W. Fittall and I. Lyskjaer and P. Ellery and P. Lombard
                      and J. Ijaz and A.-C. Strobl and D. Oukrif and M. Tarabichi
                      and M. Sill$^*$ and C. Koelsche and G. Mechtersheimer and J.
                      Demeulemeester and R. Tirabosco and F. Amary and P. J.
                      Campbell and S. Pfister$^*$ and D. T. W. Jones$^*$ and N.
                      Pillay and P. Van Loo and S. Behjati and A. M. Flanagan},
      title        = {{D}rivers underpinning the malignant transformation of
                      giant cell tumour of bone.},
      journal      = {The journal of pathology},
      volume       = {252},
      number       = {4},
      issn         = {1096-9896},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley},
      reportid     = {DKFZ-2020-01785},
      pages        = {433-440},
      year         = {2020},
      note         = {2020 Dec;252(4):433-440},
      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. This
                      article is protected by copyright. All rights reserved.},
      cin          = {B062 / HD01 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B360-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32866294},
      doi          = {10.1002/path.5537},
      url          = {https://inrepo02.dkfz.de/record/157748},
}