27 October 2013

Novel mutations define two types of bone tumour

Two related genes underlie the development of two rare bone tumours in nearly 100 per cent of patients

Prevalence and distribution of histone H3.3 somatic alterations in different tumor types. The percentage of cases in each series harboring a specific histone H3.3 alteration is indicated

Prevalence and distribution of histone H3.3 somatic alterations in different tumor types. The percentage of cases in each series harboring a specific histone H3.3 alteration is indicated [DOI: 10.1038/ng.2814]


Scientists have made a rare discovery that allows them to attribute two types of tumour almost entirely to specific mutations that lie in two related genes.

These mutations are found in nearly 100 per cent of patients suffering from two rare bone tumours; chondroblastoma and giant cell tumour of the bone.

Chondroblastoma and giant cell tumour of bone are benign bone tumours that primarily affect adolescents and young adults, respectively. They can be extremely debilitating tumours and recur despite surgery. Occasionally, these tumours can be difficult to differentiate from highly malignant bone cancers. The mutations found in this study may be used for diagnosis of chondroblastoma and giant cell tumour. In addition, the mutations offer a starting point into research for a specific treatment against these tumours.

"This is an exceptional, if not a once in a lifetime discovery for the team," says Dr Peter Campbell, co-lead author of the study from the Wellcome Trust Sanger Institute. "What we normally see is that the same mutations occur in many different types of tumour. These mutations, however, are highly specific to these tumours. Moreover, our findings suggest that these mutations are the key, if not the sole, driving force behind these tumours."

The team sequenced the full genomes of six chondroblastoma tumours and found that all six tumours had mutations in one of two related genes, H3F3A and H3F3B, which produce an identical protein, called histone 3.3.

" The high prevalence of these mutations in each tumour type is striking, but what's most remarkable is the unprecedented specificity of these mutations "

Dr Sam Behjati

Extending the study to more chondroblastoma tumours and to other bone tumours, they were able to verify that this mutation was found in almost all cases of chondroblastoma. Interestingly, the team also observed that most cases of a different type of bone tumour, giant cell tumour of bone, have a mutation in the H3F3A gene, albeit in a different position in the gene. A pattern emerged where both tumour types, chondroblastoma and giant cell tumour of bone, are defined by specific histone 3.3 mutations.

The team pinpointed the specificity of these mutations to affecting a single amino acid residue on the histone 3.3 protein; G34W amino acid residue underlies giant cell tumour of the bone and K36M amino acid residue underlies chondroblastoma.

"The high prevalence of these mutations in each tumour type is striking, but what's most remarkable is the unprecedented specificity of these mutations," says Dr Sam Behjati, first author from the Wellcome trust Sanger Institute. "The specificity of the mutations not only informs us about how these tumours develop, but also points to some fundamental function of these genes in normal bone development."

"Our findings will be highly beneficial to clinicians as we now have a diagnostic marker to differentiate chondroblastoma and giant cell tumour of bones from other bone tumours," says Professor Adrienne Flanagan, co-lead author from the Royal National Orthopaedic Hospital, and UCL Cancer Institute. "This study highlights the importance of continuing to sequence all types of human cancer."

"We are also extremely grateful to our patients and collaborators, without their help we would not have been able to study these extremely rare diseases," adds Professor Flanagan.

Notes to Editors

The Skeletal Cancer Action Trust (Scat) is a small charity, based in the heart of the RNOH with the bone cancer (Sarcoma) team. Scat is unique in its offering of high performance limbs (C-limbs) to teenagers and young adults.


Publication details

  • Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.

    Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, Nik-Zainal S, Martin S, McLaren S, Goody V, Goodie V, Robinson B, Butler A, Teague JW, Halai D, Khatri B, Myklebost O, Baumhoer D, Jundt G, Hamoudi R, Tirabosco R, Amary MF, Futreal PA, Stratton MR, Campbell PJ and Flanagan AM

    Nature genetics 2013;45;12;1479-82


This work was supported by funding the Wellcome Trust, and Skeletal Cancer Action Trust (SCAT), UK, and Rosetrees Trust UK.

Participating Centres

  • Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK
  • Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY
  • University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK
  • Universitätsklinik für Orthopädie und Orthopädische Chirurgie, Medizinische Universität, Graz, Austria
  • Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK
  • Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Herestraat 49 box 602, B-3000 Leuven, Belgium
  • Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital,
  • The Norwegian Radium Hospital, Oslo, Norway
  • Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Switzerland
  • Department of Haematology, Addenbrooke's Hospital, Cambridge, UK
  • Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY


Scat is a unique charity which supports research into the cause and treatment of musculoskeletal tumours. Scat's 'Live life to the Full' project also tries to enhance the lives of young people who have been afflicted with this disease and fund patients who suffered the terrible trauma of amputation with high performance limbs. In addition to Scat's 'Live Life' campaign, the charity also prime pumps key research projects, particularly regarding the DNA of bone cancer and improvements in treatment. Scat believes that research is our investment in fighting back, armed with more information and knowledge, in the hope of prevention and cure. Partners include UCL and The Wellcome Sanger Institute.

Scat is an effective, small charity in the heart of the Sarcoma Unit of the RNOH that relies heavily on every donor and fundraiser in its work to change lives of bone cancer patients both now and in the future. Donations can be made via Virgin Moneygiving on the home page of



The RNOH is the largest specialist orthopaedic hospital in the UK and is regarded as a leader in the field of orthopaedics. The Trust provides a comprehensive and unique range of neuro-musculoskeletal healthcare, ranging from acute spinal injuries to orthopaedic medicine and specialist rehabilitation for chronic back pain sufferers. RNOH has the largest spinal surgery service in Europe with a third of UK spinal scoliosis surgery and two thirds of specialist peripheral nerve injury work.


The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.


The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.


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