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Cited by 193Cancer-related Molecular PathwaysSarcoma Diagnosis and TreatmentDNA Repair Mechanisms

The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability

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Overholtzer, Michael, Rao, Pulivarthi H., Favis, Reyna, Lu, Xin-Yan, Elowitz, Michael B., Barany, Francis, Ladanyi, Marc, Gorlick, Richard +1 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1934852100PMC PMC208795
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Abstract

The p53 gene is a critical tumor suppressor that is inactivated in a majority of cancers. The central role of p53 in response to stresses such as DNA damage, hypoxia, and oncogene activation underlies this high frequency of negative selection during tumorigenic transformation. Mutations in p53 disrupt checkpoint responses to DNA damage and result in the potential for destabilization of the genome. Consistent with this, p53 mutant cells have been shown to accumulate genomic alterations in cell culture, mouse models, and some human tumors. The relationship between p53 mutation and genomic instability in human osteosarcoma is addressed in this report. Similar to some other primary human tumors, the mutation of p53 correlates significantly with the presence of high levels of genomic instability in osteosarcomas. Surprisingly, osteosarcomas harboring an amplification of the HDM2 oncogene, which inhibits the tumor-suppressive properties of p53 , do not display high levels of genomic instability. These results demonstrate that the inactivation of p53 in osteosarcomas directly by mutation versus indirectly by HDM2 amplification may have different cellular consequences with respect to the stability of the genome.

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  • Loss of TP53 and RB1 likely occurs early in osteosarcoma transformation, with TP53 inactivation required to propagate abnormal genomes, followed by rapid accumulation of driver lesions such as MYC amplification, PTEN loss and deletion of ATRX.

    “Using these genomic aberrations to infer the evolution of the tumours, loss of TP53 and RB1 likely occurs early in the transformation process (with TP53 inactivation required to propagate abnormal genomes 39,40,41 ), followed by rapid accumulation of driver lesions such as MYC amplification, PTEN loss 42 and deletion of ATRX”

    From Osteosarcoma (2022) · cites this paper as [39]

  • The most likely order of events for osteosarcoma evolution is loss of TP53 and RB1 as early events, with TP53 loss likely initiating genomic instability, followed by whole-genome doubling, gain of 8q (CMYC) and loss of 10q (PTEN).

    “The most likely order of events for osteosarcoma evolution is loss of TP53 and RB1 as early events, of which TP53 loss is likely the initiator of genomic instability 39,40,41 followed by whole-genome doubling, gain of 8q (CMYC) and loss of 10q (PTEN) 42 .”

    From Osteosarcoma (2022) · cites this paper as [39]

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Authors
Overholtzer, M., Rao, P. H., Favis, R., Lu, X.-Y., Elowitz, M. B., Barany, F., Ladanyi, M., Gorlick, R., & Levine, A. J.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-09-12
Volume
100
Issue
20
Pages
11547-11552
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1934852100
PMC
PMC208795
OpenAlex
W2081144759
Cited by
193
References
59
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 16 · 2019: 8 · 2018: 7 · 2017: 5 · 2016: 17 · 2015: 16 · 2014: 11 · 2013: 9 · 2012: 12
FWCI
3.29
Type
journal article
Language
en
Update notices
correction (2003-10-29)
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
TP53 mutation, osteosarcoma, genomic instability, tumor suppressor inactivation, MDM2, DNA damage checkpoint
MeSH terms
DNA, Neoplasm, Humans, Mutation, Nuclear Proteins, Nucleic Acid Hybridization, Proto-Oncogene Proteins, Osteosarcoma, Polymerase Chain Reaction, Genes, p53, Genome, Proto-Oncogene Proteins c-mdm2

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