Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma
Open accessAbstract
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor ( IGF1R ) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
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The single most frequently altered gene in osteosarcoma is TP53, which is lost in more than 90% of tumours, with most losses through intron 1 rearrangements or deletions rather than point mutations.
“The single most frequently altered gene is the tumour suppressor TP53, which is lost in >90% of osteosarcoma tumours, with the majority lost through intron 1 rearrangements or deletions rather than through point mutations 33,36,38 .”
From Osteosarcoma (2022) · cites this paper as [38]
Large-scale sequencing has identified only moderate levels of point mutations in osteosarcoma, with few recurrently mutated genes.
“large-scale sequencing has identified only moderate levels of point mutations with few recurrently mutated genes 33,34,36,38 .”
From Osteosarcoma (2022) · cites this paper as [38]
IGF1 receptor amplifications occur in up to 14% of patients with osteosarcoma and seem to drive activation of the PI3K-AKT-mTOR pathway through the MAPK pathway.
“Indeed, IGF1 receptor amplifications occur in up to 14% of patients with osteosarcoma 38 , which seems to drive activation of the PI3K-AKT-mTOR pathway through the MAPK pathway 98 .”
From Osteosarcoma (2022) · cites this paper as [38]
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- Tarpey P. S.. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat. Genet. 45, 923– U293 (2013). 23770606 PMC3743157
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- Authors
- Behjati, S., Tarpey, P. S., Haase, K., Ye, H., Young, M. D., Alexandrov, L. B., Farndon, S. J., Collord, G., Wedge, D. C., Martincorena, I., Cooke, S. L., Davies, H., Mifsud, W., Lidgren, M., Martin, S., Latimer, C., Maddison, M., Butler, A. P., Teague, J. W., Pillay, N., Shlien, A., McDermott, U., Futreal, P. A., Baumhoer, D., Zaikova, O., Bjerkehagen, B., Myklebost, O., Amary, M. F., Tirabosco, R., Van Loo, P., Stratton, M. R., Flanagan, A. M., & Campbell, P. J.
- Affiliations
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- The Francis Crick Institute (GB)
- Royal National Orthopaedic Hospital NHS Trust (GB)
- Los Alamos National Laboratory (US)
- Centre for Human Genetics (GB)
- University College London (GB)
- Hospital for Sick Children (CA)
- The University of Texas MD Anderson Cancer Center (US)
- University of Basel (CH)
- Oslo University Hospital (NO)
- Corresponding author
- Campbell, Peter J.
- ORCID
- Behjati, Sam
- Tarpey, Patrick S.
- Haase, Kerstin
- Ye, Hongtao
- Young, Matthew D.
- Alexandrov, Ludmil B.
- Farndon, Sarah J.
- Collord, Grace
- Wedge, David C.
- Davies, Helen
- Mifsud, William
- Martin, Sancha
- Latimer, Calli
- Teague, Jon W.
- Pillay, Nischalan
- Shlien, Adam
- McDermott, Ultan
- Futreal, P. Andrew
- Baumhoer, Daniel
- Zaikova, Olga
- Bjerkehagen, Bodil
- Myklebost, Ola
- Tirabosco, Roberto
- Van Loo, Peter
- Stratton, Michael R.
- Flanagan, Adrienne M.
- Campbell, Peter J.
- Venue
- Nature Communications
- Published
- 2017-06-23
- Volume
- 8
- Issue
- 1
- Pages
- 15936-15936
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5490007
- OpenAlex
- W2671688469
- Cited by
- 261
- References
- 33
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 23 · 2023: 29 · 2022: 20 · 2021: 42 · 2020: 37 · 2019: 33 · 2018: 24 · 2017: 8
- FWCI
- 22.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- St. Baldrick's Foundation
- Wellcome Trust (FC001202, 110104/Z/15/Z)
- Francis Crick Institute (FC001202, 10202)
- Cancer Research UK (18387, FC001202, 21777)
- National Institute for Health and Care Research (NF-SI-0616-10112)
- Rosetrees Trust (M46‐F1, M23-F1)
- CHILDREN with CANCER UK
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (MR/N005813/1, FC001202)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- osteosarcoma, IGF1R inhibitors, chromothripsis, genome rearrangement, driver mutations, histological subtypes, mutational mechanisms
- MeSH terms
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Insulin-Like Growth Factor I, Male, Middle Aged, Mutation, Osteosarcoma, Gene Rearrangement, Signal Transduction, In Situ Hybridization, Fluorescence, Receptor, IGF Type 1, Young Adult
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