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Comprehensive Mapping of p53 Pathway Alterations Reveals an Apparent Role for Both SNP309 and MDM2 Amplification in Sarcomagenesis
Published version of a preprint
Abstract
Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. Results: We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification. Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists. Clin Cancer Res; 17(3); 416–26. ©2010 AACR.
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“Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours3–10 (Table 1).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [8]
In the citing paper
“The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [8]
Citations
Cites
Baltosser, W. H., & Zar, J. H. (1996) · Ecology · doi:10.2307/2265725 · Cited by 35,166
Zar, J. H. (1996) · Cited by 7,837
Biostatistical Analysis (2nd ed.).
Breen, T. J., & Zar, J. H. (1986) · Journal of the American Statistical Association · doi:10.2307/2289268 · Cited by 5,792
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 1×
“A central regulator of p53 is the proto-oncogene Mdm2, which functions as an E3 ubiquitin ligase promoting p53 degradation (3, 4).”
BackgroundPetitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S. V., Hainaut, P., & Olivier, M. (2007) · Human Mutation · doi:10.1002/humu.20495 · Cited by 1,598 · cited 4×
“Somatic p53 mutations have been reported in 20% to 33% of all sarcomas (2, 18).”
BackgroundInfluentialTumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286
Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.022 · Cited by 1,265
Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2
Kamijo, T., Weber, J. D., Zambetti, G., Zindy, F., Roussel, M. F., & Sherr, C. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8292 · Cited by 899
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
p53 polymorphisms: cancer implications
Whibley, C., Pharoah, P. D. P., & Hollstein, M. C. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2584 · Cited by 677
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648
Inactivation of the p53 pathway in retinoblastoma
Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., et al. (2006) · Nature · doi:10.1038/nature05194 · Cited by 595
p53 Mutation and MDM2 amplification in human soft tissue sarcomas.
Leach, F. S., Tokino, T., Meltzer, P. S., Burrell, M., Oliner, J., Smith, S., HILL, D. E., Sidransky, D., Kinzler, K. W., & Vogelstein, B. (1993) · PubMed · Cited by 533
BRAF Mutation in Metastatic Colorectal Cancer
Tol, J., Nagtegaal, I. D., & Punt, C. J. A. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0904160 · Cited by 445
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Nature · doi:10.1038/nature05077 · Cited by 382
Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352
Mutation spectrum of the p53 gene in bone and soft tissue sarcomas.
Toguchida, J., Yamaguchi, T., Ritchie, B., Beauchamp, R. L., Dayton, S. H., Herrera, G. E., Yamamuro, T., Kotoura, Y., Sasaki, M. S., & Little, J. B. (1992) · PubMed · Cited by 297
Molecular Pathogenesis of Osteosarcoma
Kansara, M., & Thomas, D. M. (2007) · DNA and Cell Biology · doi:10.1089/dna.2006.0505 · Cited by 280
Self-citationWell-differentiated and dedifferentiated liposarcomas
Coindre, J., Pédeutour, F., & Aurias, A. (2009) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-009-0815-x · Cited by 254
Singer, S., Socci, N. D., Ambrosini, G., Sambol, E. B., DeCarolis, P. L., Wu, Y. V., O’Connor, R., Maki, R. G., Viale, A. J., Sander, C., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0584 · Cited by 249
The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H., & DePinho, R. A. (2004) · Oncogene · doi:10.1038/sj.onc.1207074 · Cited by 224 · cited 1×
“Germline inactivation of ARF results in tumor development in mice, and bypasses the need for inactivation of p53 to immortalize fibroblasts (10, 11).”
BackgroundWang, T., Maierhofer, C., Speicher, M. R., Lengauer, C., Vogelstein, B., Kinzler, K. W., & Velculescu, V. E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202610899 · Cited by 224
Chelala, C., Khan, A., & Lemoine, N. R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btn653 · Cited by 200
Tsuchiya, T., Sekine, K., Hinohara, S.-I., Namiki, T., Nobori, T., & Kaneko, Y. (2000) · Cancer Genetics and Cytogenetics · doi:10.1016/s0165-4608(99)00255-1 · Cited by 177
Italiano, A., Bianchini, L., Gjernes, E., Keslair, F., Ranchère‐Vince, D., Dumollard, J., Haudebourg, J., Leroux, A., Mainguene, C., Terrier, P., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-3185 · Cited by 142
Targeted mutation of p53 and Rb in mesenchymal cells of the limb bud produces sarcomas in mice
Lin, P. P., Pandey, M. K., Jin, F., Raymond, A. K., Akiyama, H., & Lozano, G. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp180 · Cited by 122
Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Müller, C. R., Paulsen, E. B., Noordhuis, P., Pedeutour, F., Sæter, G., & Myklebost, O. (2007) · International Journal of Cancer · doi:10.1002/ijc.22643 · Cited by 119
Costa, S., Pinto, D., Pereira, D., Rodrigues, H., Cameselle‐Teijeiro, J., Medeiros, R., & Schmitt, F. C. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-32 · Cited by 114
Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome
Palmero, E. I., Achatz, M. I., Ashton‐Prolla, P., Olivier, M., & Hainaut, P. L. (2009) · Current Opinion in Oncology · doi:10.1097/cco.0b013e328333bf00 · Cited by 105
Mælandsmo, G. M., Berner, J. M., Flørenes, V. A., Forus, A., Hovig, E. J., Fodstad, Ø., & Myklebost, O. (1995) · British Journal of Cancer · doi:10.1038/bjc.1995.344 · Cited by 102
Rubio, R., Garcı́a-Castro, J., Gutiérrez-Aranda, I., Paramio, J. M., Santos, M., Catalina, P., Leone, P., Menéndez, P. R., & Rodrı́guez, R. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4640 · Cited by 102
Saddler, C. M., Ouillette, P. D., Kujawski, L. A., Shangary, S. K., Talpaz, M., Kaminski, M. S., Erba, H. P., Shedden, K., Wang, S., & Malek, S. N. (2007) · Blood · doi:10.1182/blood-2007-09-112698 · Cited by 96
MDM2 and MDMX can interact differently with ARF and members of the p53 family
Wang, X., Arooz, T., Siu, W. Y., Chiu, C. H. S., Lau, A., Yamashita, K., & Poon, R. Y. C. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02124-x · Cited by 94
Bartel, F., Schulz, J., Böhnke, A., Blümke, K., Kappler, M., Bache, M., Schmidt, H., Würl, P., Taubert, H. W., & Hauptmann, S. (2005) · International Journal of Cancer · doi:10.1002/ijc.21206 · Cited by 93
Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities
Barboza, J., Iwakuma, T., Terzian, T., El‐Naggar, A. K., & Lozano, G. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-2079 · Cited by 91
Katano, H., Sato, Y., & Sata, T. (2001) · Cancer · doi:10.1002/1097-0142(20011215)92:12 · Cited by 81
Oda, Y., Yamamoto, H., Takahira, T., Kobayashi, C., Kawaguchi, K., Tateishi, N., Nozuka, Y., Tamiya, S., Tanaka, K., Matsuda, S., et al. (2005) · The Journal of Pathology · doi:10.1002/path.1848 · Cited by 76
MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation
Jackson, M. W., Lindström, M. S., & Berberich, S. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010685200 · Cited by 74
Alterations of INK4A and INK4B Genes in Adult Soft Tissue Sarcomas: Effect on Survival
Orlow, I., Drobnjak, M., Zhang, Z., Lewis, J., Woodruff, J. M., Brennan, M. F., & Cordon‐Cardo, C. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.1.73 · Cited by 69
No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer
Campbell, I., Eccles, D., & Choong, D. Y. H. (2005) · Cancer Letters · doi:10.1016/j.canlet.2005.09.003 · Cited by 69
Walter, H., Radig, K., Ryś, J., Bosse, A., Kuhnen, C., Hoang‐Vu, C., Roessner, A., & Schneider‐Stock, R. (1998) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s004320050211 · Cited by 67
DNA hypermethylation status of multiple genes in soft tissue sarcomas
Kawaguchi, K., Oda, Y., Saito, T., Yamamoto, H., Takahira, T., Kobayashi, C., Tamiya, S., Tateishi, N., Iwamoto, Y., & Tsuneyoshi, M. (2005) · Modern Pathology · doi:10.1038/modpathol.3800502 · Cited by 66
Toffoli, G., Biason, P., Russo, A. G., Mattia, E. D., Cecchin, E., Hattinger, C. M., Pasello, M., Alberghini, M., Ferrari, C., Scotlandi, K., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2249 · Cited by 61
Aberrant Methylation of p14ARF Gene Correlates with Poor Survival in Osteosarcoma
Oh, J. H., Kim, H.-S., Kim, H., Kim, W. H., & Lee, S. H. (2006) · Clinical Orthopaedics and Related Research · doi:10.1097/01.blo.0000188063.56091.69 · Cited by 52
Polymorphisms in TP53 and MDM2 combined are associated with high grade endometrial cancer
Ashton, K. A., Proietto, A. M., Otton, G. R., Symonds, I., McEvoy, M., Attia, J., Gilbert, M. B., Hamann, U., & Scott, R. J. (2009) · Gynecologic Oncology · doi:10.1016/j.ygyno.2008.12.036 · Cited by 45
Talseth‐Palmer, B. A., Meldrum, C. J., Suchy, J., Kurzawski, G., Lubiński, J., & Scott, R. J. (2006) · International Journal of Cancer · doi:10.1002/ijc.22339 · Cited by 44
High prevalence of p53 exon 4 mutations in soft tissue sarcoma
Das, P. K., Kotilingam, D., Korchin, B., Liu, J., Yu, D., Lazar, A. J., Pollock, R. E., & Lev, D. C. (2007) · Cancer · doi:10.1002/cncr.22680 · Cited by 37
Tumor suppression by ARF: Gatekeeper and caretaker
Dominguez‐Brauer, C., Brauer, P. M., Chen, Y., Pimkina, J. S., & Raychaudhuri, P. (2010) · Cell Cycle · doi:10.4161/cc.9.1.10350 · Cited by 37
Torquato, S. (2002) · Interdisciplinary applied mathematics · doi:10.1007/978-1-4757-6355-3_1 · Cited by 31
Zaykin, D. V., & Young, S. S. (2005) · Pharmacogenomics · doi:10.1517/14622416.6.1.77 · Cited by 18
Self-citationYoung, S. S., & Ge, N. (2005) · Pharmacogenomics · doi:10.1517/14622416.6.1.65 · Cited by 15
Self-citation
Research works printed but not linked: 1
- Brown, 2009, Awakening guardian angels: drugging the p53 pathway, Nat Rev Cancer, 9, 862, 10.1038/nrc2763 · DOI · Paper page
Cited by
Sorted by citations
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279
Advances in sarcoma genomics and new therapeutic targets
Taylor, B. S., Barretina, J., Maki, R. G., Antonescu, C. R., Singer, S., & Ladanyi, M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3087 · Cited by 444
FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor
Guagnano, V., Kauffmann, A., Wöhrle, S., Stamm, C., Ito, M., Barys, L., Pornon, A., Yao, Y., Li, F., Zhang, Y., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0210 · Cited by 345
Self-citationIntegrative genomic and transcriptomic analysis of leiomyosarcoma
Chudasama, P., Mughal, S. S., Sanders, M. A., Hübschmann, D., Chung, I., Deeg, K. I., Wong, S.-H., Rabe, S., Hlevnjak, M., Zapatka, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02602-0 · Cited by 316
Lechner, M., Frampton, G. M., Fenton, T. R., Feber, A., Palmer, G. A., Jay, A., Pillay, N., Forster, M. D., Cronin, M. T., Lipson, D., et al. (2013) · Genome Medicine · doi:10.1186/gm453 · Cited by 219
Metadata
- Authors
- Ito, M., Barys, L., O'Reilly, T., Young, S., Gorbatcheva, B., Monahan, J., Zumstein-Mecker, S., Choong, P. F., Dickinson, I., Crowe, P., Hemmings, C., Desai, J., Thomas, D. M., & Lisztwan, J.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Authors' Affiliations: 1Novartis Institutes for Biomedical Research, Oncology Research, Basel, Switzerland; 2Peter MacCallum Cancer Centre, Melbourne, Australia; 3Novartis Institutes for Biomedical Research, Oncology Translational Medicine, Cambridge, Massachusetts; 4Wesley Research Institute, Brisbane, Australia; 5Prince of Wales Hospital, Sydney, Australia; and 6Canberra Hospital, Canberra, Australia
- Venue
- Clinical Cancer Research
- Published
- 2011-02-01
- Volume
- 17
- Issue
- 3
- Pages
- 416-426
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2056955003
- Cited by
- 115
- References
- 57
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 9 · 2015: 17 · 2014: 16 · 2013: 10 · 2012: 10
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- p53 pathway, sarcomagenesis, soft tissue sarcoma, MDM2 amplification, TP53 mutation, CDKN2A, MDM2 SNP309, liposarcoma, lipoma, leiomyosarcoma, osteosarcoma, sarcoma subtypes, MDM2 inhibitors, tumor suppressor inactivation
- MeSH terms
- Bone Neoplasms, Chromosome Mapping, Gene Amplification, Humans, Mutation, Sarcoma, Soft Tissue Neoplasms, Biomarkers, Tumor, Genes, p53, Gene Dosage, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-mdm2
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