Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma
Open accessAbstract
Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%-53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.
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The genomic landscape of osteosarcoma tumours is usually dominated by widespread structural rearrangements, suggesting that several mutational mechanisms, including chromothripsis, chromoplexy, kataegis and other structure-altering mechanisms, are involved.
“The genomic landscape of osteosarcoma tumours is usually dominated by widespread structural rearrangements, suggesting that several different mutational mechanisms, including chromothripsis, chromoplexy, kataegis and other structure-altering mechanisms, are involved 32,33,34 .”
From Osteosarcoma (2022) · cites this paper as [33]
Deletion of RB1 occurs in up to 30% of osteosarcoma tumours, often through loss of heterozygosity.
“Deletion of RB1 also occurs in up to 30% of osteosarcoma tumours, often through loss of heterozygosity (LOH) 33,34 .”
From Osteosarcoma (2022) · cites this paper as [33]
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 [33]
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 [33]
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References 41 · Cited by 752
Research works printed but not linked: 2
- Chen X Steward E Shelat A Qu C Bahrami A Hatley M Wu G Bradley C McEvoy J Pappo A 2013 RAS Pathway Mutations are Associated with High-Risk Embryonal Rhabdomyosarcoma Cancer Cell in press
- Downing JR Wilson RK Zhang J Mardis ER Pui CH Ding L Ley TJ Evans WE 2012b The Pediatric Cancer Genome Project Nature genetics 44 619 622 22641210 PMC3619412
- Authors
- Chen, X., Bahrami, A., Pappo, A., Easton, J., Dalton, J., Hedlund, E., Ellison, D., Shurtleff, S., Wu, G., Wei, L., Parker, M., Rusch, M., Nagahawatte, P., Wu, J., Mao, S., Boggs, K., Mulder, H., Yergeau, D., Lu, C., Ding, L., Edmonson, M., Qu, C., Wang, J., Li, Y., Navid, F., Daw, N. C., Mardis, E. R., Wilson, R. K., Downing, J. R., Zhang, J., & Dyer, M. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Washington University in St. Louis (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Zhang, Jinghui
- Dyer, Michael A.
- ORCID
- Chen, Xiang
- Bahrami, Armita
- Pappo, Alberto
- Easton, John
- Dalton, James
- Ellison, David
- Wu, Gang
- Wei, Lei
- Parker, Matthew
- Rusch, Michael
- Wu, Jianrong
- Boggs, Kristy
- Mulder, Heather
- Yergeau, Donald
- Lu, Charles
- Ding, Li
- Edmonson, Michael
- Qu, Chunxu
- Wang, Jianmin
- Navid, Fariba
- Daw, Najat C.
- Mardis, Elaine R.
- Wilson, Richard K.
- Downing, James R.
- Zhang, Jinghui
- Dyer, Michael A.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 7
- Issue
- 1
- Pages
- 104-112
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4096827
- OpenAlex
- W2010256904
- Cited by
- 752
- References
- 41
- Citations by year
- 2026: 47 · 2025: 52 · 2024: 50 · 2023: 85 · 2022: 62 · 2021: 84 · 2020: 79 · 2019: 68 · 2018: 49 · 2017: 56 · 2016: 55 · 2015: 52 · 2014: 12
- FWCI
- 46.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (EY014867, R01EY014867, R01EY018599, EY018599, F32EY006803)
- National Cancer Institute (R01CA168875, CA168875, CA21765, P30CA021765)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- pediatric osteosarcoma, somatic structural variants, copy number alterations, kataegis, p53 pathway, RB1, ATRX, DLG2, somatic mutations, carcinogenesis
- MeSH terms
- Adolescent, Bone Neoplasms, Child, Child, Preschool, DNA, Neoplasm, Humans, Mutation, Neoplasm Metastasis, Osteosarcoma, Genome, Human, Disease Progression, Polymorphism, Single Nucleotide, DNA Copy Number Variations, Carcinogenesis
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