Genetic discovery will help clinicians identify aggressive versus benign bone tumours
A genetic change affecting the transcription factor, FOS is specific to osteoblastoma, distinguishing it from osteosarcoma
The first genetic marker for the bone tumour, osteoblastoma, has been discovered by scientists at the Wellcome Sanger Institute and their collaborators. Whole-genome and transcriptome sequencing of human bone tumours revealed that a genetic change that affects the transcription factor, FOS, is a hallmark mutation of osteoblastoma.
The results, published in Nature Communications, will help clinicians correctly distinguish benign osteoblastoma tumours from aggressive osteosarcoma tumours and direct the correct treatment.
Osteoblastoma is the most common benign tumour of the bone, mainly affecting children and adults between the ages of 10 and 25. It is treated by surgical removal of the tumour, however the diagnosis of osteoblastoma can be challenging. Under the microscope, osteoblastoma tumours can look very similar to osteosarcoma, an aggressive form of bone cancer that requires extensive treatment, sometimes including amputation or significant surgery and chemotherapy.
In this new study, scientists from the Wellcome Sanger Institute and their collaborators at the UCL Cancer Institute and Francis Crick Institute discovered a genetic mutation that distinguishes osteoblastoma from osteosarcoma.
The team carried out whole genome and whole transcriptome* sequencing on five osteoblastoma tumours and one osteoid osteoma tumour.
Researchers discovered a mutation that affects FOS, a transcription factor that turns on and off genes to ensure they are expressed in the right cell at the right time, as well as its relative, FOSB.
When the team extended their results in a study of 55 cases they found that mutations in FOS and FOSB are ubiquitous across osteoblastoma and osteoid osteoma.
To explore whether their result could be useful as diagnostic markers for osteoblastoma, scientists examined the whole genome sequences of 55 osteosarcoma cases, and found none of the samples harboured mutations in FOS or FOSB. When the team analysed over 2,500 non-osteoblastoma tumours, they again did not find similar mutations, meaning the FOS and FOSB mutations are specific to osteoblastoma.
“The main clinical challenge when diagnosing osteoblastoma can be to reliably distinguish these tumours from osteosarcoma. These two forms of bone tumour require very different treatments: osteoblastoma tumours just need removing to ease symptoms, whereas osteosarcomas is treated aggressively with surgery and intensive chemotherapy. For the first time, we have discovered a specific mutation that defines osteoblastoma.”
Dr Sam Behjati Co-lead author from the Wellcome Sanger Institute and University of Cambridge
“We have known for a while that FOS is involved in the progression of bone tumours, however we have not found mutations of FOS in human bone-forming tumours before. Using genomic sequencing we have shown that mutations in FOS and its relative FOSB are diagnostic markers of osteoblastoma.”
Dr Matthew Fittall Co-first author from the Francis Crick Institute, UCL Cancer Institute and Wellcome Sanger Institute
“Genomics is transforming our understanding of cancers. Our discovery of the genetic mutation that characterises osteoblastoma will help clinicians diagnose it with more confidence and direct the correct treatment.”
Professor Adrienne Flanagan Co-lead author from the UCL Cancer Institute and Royal National Orthopaedic Hospital NHS Trust
*The transcriptome is all of the messenger RNA molecules expressed from the genes of an organism. By analysing the transcriptome, researchers can determine when and where each gene is turned on or off in the cells and tissues of an organism.
This work was supported by Wellcome, the Skeletal Cancer Action Trust UK, the Royal National Orthopaedic Hospital NHS Trust and Rosetrees Trust.
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London. The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe. The Francis Crick Institute will be world-class with a strong national role. Its distinctive vision for excellence includes commitments to collaboration; to developing emerging talent and exporting it to the rest of the UK; to public engagement; and to helping turn discoveries into treatments as quickly as possible to improve lives and strengthen the economy. www.crick.ac.uk/
UCL was founded in 1826. We were the first English university established after Oxford and Cambridge, the first to open up university education to those previously excluded from it, and the first to provide systematic teaching of law, architecture and medicine. We are among the world’s top universities, as reflected by performance in a range of international rankings and tables. UCL currently has over 39,000 students from 150 countries and over 12,500 staff. Our annual income is more than £1 billion. www.ucl.ac.uk | Follow us on Twitter @uclnews | Watch our YouTube channel YouTube.com/UCLTV
UCL Cancer Institute, London, is the hub for cancer research at University College London (UCL), one of the world’s leading universities. The UCL Cancer Institute draws together over 300 researchers/clinicians working to translate research discoveries into new strategies to prevent, diagnose and treat cancer. www.ucl.ac.uk/cancer/
The RNOH is the largest specialist orthopaedic hospital in the UK, and a recognised world leader in the field of orthopaedics and neuro-musculoskeletal medicine. It treats more than 125,000 patients a year for conditions ranging from acute spinal injuries and bone cancer to prosthetic rehabilitation and chronic back pain. http://www.rnoh.nhs.uk/
The Wellcome 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. To celebrate its 25th year in 2018, the Institute is sequencing 25 new genomes of species in the UK. Find out more at www.sanger.ac.uk or follow @sangerinstitute
Wellcome exists to improve health for everyone by helping great ideas to thrive. We’re a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. wellcome.org
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