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Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database
Open accessAbstract
The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.
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“TP53 co-mutations are associated with an inflamed tumor immune microenvironment and increased tumor cell PD-L1 expression in KRAS-mutant NSCLC and GEMMs.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [144]
In the citing paper
“the vast majority of these mutations have previously been identified as pathogenic10.”
From Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2015) · cites this paper as [10]
Citations
Cites
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“The tumor suppressor gene TP53 (OMIM ]191117) encodes a transcription factor that responds to several forms of cellular stress and exerts multiple, antiproliferative functions [Vogelstein et al., 2000].”
BackgroundGerm Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms
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“Inherited TP53 mutations predispose to a wide spectrum of early-onset cancers and are associated with Li-Fraumeni and Li-Fraumeni-like syndrome (LFS and LFL, respectively) [Malkin et al., 1990].”
BackgroundPreferential Formation of Benzo[ a ]pyrene Adducts at Lung Cancer Mutational Hotspots in P53
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“In lung cancers, V157F, R158L, R248L, and R273L hotspots are due to G4T transversions that have been shown to be caused by the presence of benzo(a)-pyrene diol epoxide (BPDE) adducts on guanines at these codons [Denissenko et al., 1996].”
BackgroundMutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
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“Studies in mouse models of LFS have reported evidence of GOF for R175H and R273H mutants [Lang et al., 2004; Olive et al., 2004].”
BackgroundThe IARC TP53 database: new online mutation analysis and recommendations to users
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“It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients [Olivier et al., 2002].”
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“Studies in mouse models of LFS have reported evidence of GOF for R175H and R273H mutants [Lang et al., 2004; Olive et al., 2004].”
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“Somatic TP53 gene alterations are frequent in most human cancers [Hainaut and Hollstein, 2000], ranging from 5 to 80% depending on the type, stage, and etiology of tumors.”
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“…2007 WILEY-LISS, INC. and a single study has performed a systematic analysis of the activity of all possible missense mutations produced by singlenucleotide substitution in the entire sequence of TP53 (2,314 mutations) on eight different p53-RE in yeast cells [Kato et al., 2003].”
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Olivier, M., Langer√∏d, A., Carrieri, P., Bergh, J. C. S., Klaar, S., Eyfjord, J. E., Theillet, C. G., Rodríguez, C., Lidereau, R., Bièche, I., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1029 · Cited by 590 · cited 1×
“However, in a recent study on a large series of patients with breast cancer, we found that TP53 mutations were an independent factor of poor prognosis [Olivier et al., 2006], but that TA did not accurately predict differences in survival among patients with TP53 mutations.”
ResultSelf-citationOlivier, M., Goldgar, D. E., Sodha, N., Ohgaki, H., Kleihues, P., Hainaut, P. L., & Eeles, R. A. (2003) · PubMed · Cited by 480
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Cai, H., Jing, C., Chang, X., Ding, D., Han, T., Yang, J., Lu, Z., Hu, X., Liu, Z., Wang, J., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1941-0 · Cited by 115
Exploiting synthetic lethal interactions for targeted cancer therapy
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“We started by focusing on cells that were deficient for the prominent tumor suppressor gene p53, which is lost in approximately 30% of all human tumors.(49) We then identified multiple components of the DNA damage response signaling network that are synthetic lethal with loss of p53 in the context of DNA damaging chem…”
BackgroundTumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection
Siegl, C., Prusty, B. K., Rajeeve, K., Wischhusen, J., & Rudel, T. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.004 · Cited by 116
Functional interplay between MDM2, p63/p73 and mutant p53
Stindt, M., Muller, P. A. J., Ludwig, R., Kehrloesser, S., Dötsch, V., & Vousden, K. H. (2014) · Oncogene · doi:10.1038/onc.2014.359 · Cited by 114
“Indeed, I245R is found in the p53 database of somatic tumour mutations, albeit rarely (0.2% of all recorded somatic p53 mutations), suggesting that this mutation can be advantageous during cancer development (47).”
InfluentialRajagopalan, S., Huang, F. L., & Fersht, A. R. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq800 · Cited by 115
“p53 is mutated in 50% of cancers, and the DNA-binding domain is the main carrier of oncogenic mutations (3).”
BackgroundTP53 Germline Mutations in Adult Patients with Adrenocortical Carcinoma
Herrmann, L. J. M., Heinze, B., Fassnacht, M., Willenberg, H. S., Quinkler, M., Reisch, N., Zink, M., Allolio, B., & Hahner, S. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1982 · Cited by 109
Oza, A. M., Estevez-Diz, M., Grischke, E.-M., Hall, M., Marmé, F., Provencher, D., Uyar, D., Weberpals, J. I., Wenham, R. M., Laing, N., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-0219 · Cited by 129
“Themost common type of genetic alterations in TP53 observed in human tumors are missensemutations that result in variable levels (0%–100%) of reduced TP53 transactivation function (27).”
BackgroundTumor Protein p53 (TP53) Testing and Li-Fraumeni Syndrome
Sorrell, A., Espenschied, C. R., Culver, J. O., & Weitzel, J. N. (2013) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-013-0020-0 · Cited by 109
“TP53 is the most frequently mutated gene in human cancer [19], with the prevalence of acquired TP53 mutations being highest in epithelial ovarian cancers (47 %), colorectal cancers (43 %), head/neck cancers (42 %), and esophageal cancers (41 %) [International Agency for Research on Cancer (IARC) database, R15 release]…”
InfluentialCancer in Light of Experimental Evolution
Sprouffske, K., Merlo, L. M. F., Gerrish, P. J., Maley, C. C., & Sniegowski, P. (2012) · Current Biology · doi:10.1016/j.cub.2012.06.065 · Cited by 110
Inflammation, DNA Damage, Helicobacter pylori and Gastric Tumorigenesis
Kalisperati, P., Spanou, E., Pateras, I. S., Korkolopoulou, P. A., Varvarigou, A. A., Karavokyros, I., Gorgoulis, V. G., Vlachoyiannopoulos, P. G., & Sougioultzis, S. (2017) · Frontiers in Genetics · doi:10.3389/fgene.2017.00020 · Cited by 115
“%) and early event in sporadic gastric cancer (Ochiai et al., 1996; Petitjean et al., 2007) (Figure 1).”
BackgroundTP53 Status and Response to Chemotherapy in Breast Cancer
Bertheau, P., Espié, M., Turpin, E., Lehmann‐Che, J., Plassa, L., Varna, M., Janin, A., & de Thé, H. (2008) · Pathobiology · doi:10.1159/000123851 · Cited by 111
Unraveling the molecular genetics of head and neck cancer through genome-wide approaches
Riaz, N., Morris, L. G. T., Lee, W., & Chan, T. A.-T. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.07.002 · Cited by 111
“However, the significance of this remains unclear.(57,58) Besides mutation, p53 may be inactivated in other ways such as via MDM2 over-expression or amplification (MDM2 is a negative regulator of p53) or deletion of CDKN2A (negatively regulates MDM2).”
BackgroundPfaff, E., Remke, M., Sturm, D., Benner, A., Witt, H., Milde, T., von Bueren, A. O., Wittmann, A., Schöttler, A., Jorch, N., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.1670 · Cited by 107
“In the TP53 Database of the International Agency for Research on Cancer, the authors list a total of nine studies on the prognostic role of TP53 mutations in brain tumors (selected based on a minimum cohort size of 50 patients) and report that six of nine studies find either no association with survival (n 4) or an as…”
Influentialp53 and MDM2 in renal cell carcinoma
Noon, A. P., Vlatković, N., Polański, R., Maguire, M., Shawki, H., PARSONS, K. F., & Boyd, M. T. (2010) · Cancer · doi:10.1002/cncr.24841 · Cited by 109
“fr/ accessed June 15, 2009).(71) One intriguing observation derives from the study by Chemeris and colleagues, who observed that 0 of 29 RCC samples, all positive for p53 by IHC, had a p53 point mutation.”
BackgroundResultEvolution to plasmablastic lymphoma evades CD19‐directed chimeric antigen receptor T cells
Evans, A. G., Rothberg, P. G., Burack, R., Huntington, S. F., Porter, D. L., Friedberg, J. W., & Liesveld, J. L. (2015) · British Journal of Haematology · doi:10.1111/bjh.13562 · Cited by 105
“Both mutations were predicted to be non-functional by the International Agency for Research on Cancer (IARC) TP53 database (Petitjean et al, 2007).”
BackgroundTumor 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
Self-citationMaschietto, M. C., Williams, R. D., Chagtai, T., Popov, S. D., Sebire, N. J., Vujanic, G. M., Perlman, E. J., Anderson, J. R., Grundy, P. E., Dome, J. S., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109924 · Cited by 106
“Primer sequences, product lengths and PCR conditions for the 11 exons of TP53 were retrieved from the IARC TP53 website [20].”
MethodResultThe paradigm of mutant p53-expressing cancer stem cells and drug resistance
Shetzer, Y., Solomon, H., Koifman, G., Molchadsky, A., Horesh, S., & Rotter, V. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu073 · Cited by 105
“Rather, expression of mutant p53 (frequency of 26% in these tumor types) (76) is critical for the manifestation of the full malignant potential of these CSCs.”
BackgroundSano, D., Xie, T., Ow, T. J., Zhao, M., Pickering, C. R., Zhou, G., Sandulache, V. C., Wheeler, D. A., Gibbs, R. A., Caulı́n, C., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0046 · Cited by 105
Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53
Jordan, J. J., Menendez, D., Inga, A., Nourredine, M., Bell, D., & Resnick, M. A. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000104 · Cited by 103
“specific DNA binding domain [10,11] which can abrogate or alter”
BackgroundGain of Function of Mutant TP53 in Glioblastoma: Prognosis and Response to Temozolomide
Wang, X., Chen, J., Liu, J., You, C., Liu, Y., & Mao, Q. (2013) · Annals of Surgical Oncology · doi:10.1245/s10434-013-3380-0 · Cited by 103
Modulating epigenetic modifications for cancer therapy (Review)
Castro-Muñoz, L. J., Vázquez‐Ulloa, E., Sahlgren, C., Lizano, M., la Cruz-Hernández, E. N. D., & Contreras‐Paredes, A. (2023) · Oncology Reports · doi:10.3892/or.2023.8496 · Cited by 111
The p53-Estrogen Receptor Loop in Cancer
Berger, C. E., Qian, Y., & Chen, X. (2013) · Current Molecular Medicine · doi:10.2174/15665240113139990065 · Cited by 108
“Indeed, p53 inactivation occurs in almost all human tumors with a rate up to 80% depending on the type, stage, and etiology of cancers [4, 5].”
BackgroundDNA damage checkpoint response to aflatoxin B1
Engin, A. B., & Engin, A. (2018) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2018.12.006 · Cited by 104
Park, Y.-H., Kim, D., Dai, J., & Zhang, Z. (2015) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2015.06.008 · Cited by 104
“…the mutations result in the expression of a p53 protein that has in most cases lost wild-type functions and 2B cells, an appropriate in vitro model to study heavy metals induced 6/j.taap.2015.06.008 may exert a dominant-negative regulation over any remaining wildtype p53 (Petitjean et al., 2007).”
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“neck, bladder, colorectal and haematopoietic systems, there has been no significant association reported between p53 mutations and clinical outcome in almost half of the studies investigating brain, lung and ovarian cancers and p53 mutations are associated with good prognosis in rare cases (45).”
BackgroundMa, X., Teuff, G. L., Lacas, B., Tsao, M., Graziano, S. L., Pignon, J., Douillard, J.-Y., Chevalier, T. L., Seymour, L., Filipits, M., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.02.002 · Cited by 102
“5% of all mutations in NSCLC (2102 mutations in 2292 cases matching the definition of this study).(27) In the present study, mutations outside exons 5 to 8 were not systematically analyzed because of the lack of suitable materials for all tumors.”
BackgroundSelf-citationSer, H., Mutalib, N. A., Yin, W., Chan, K., Goh, B. H., & Lee, L. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01398 · Cited by 100
“SI value was calculated by dividing IC50 of cancer cell line with IC50 value of normal cell line.”
BackgroundMethodLi, V. D., Li, K. H. L., & Li, J. T. (2018) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-018-2817-z · Cited by 99
The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy
Nakamura, M., Obata, T., Daikoku, T., & Fujiwara, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215482 · Cited by 101
“Dysfunction of p53 has been observed in many malignant tumors [7,8].”
BackgroundThe Inherited p53 Mutation in the Brazilian PopulationPreprint
Achatz, M. I., & Zambetti, G. P. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026195 · Cited by 99
“Note the high frequency of the constitutional p.R337H mutation common in Southern Brazil (see the International Agency for Research on Cancer [IARC] TP53 database, p53.iarc.fr) (Petitjean et al. 2007).”
BackgroundClinical Relevance of Gain-Of-Function Mutations of p53 in High-Grade Serous Ovarian Carcinoma
Kang, H. J., Chun, S., Kim, K.-R., Sohn, I., & Sung, C. O. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072609 · Cited by 98
“Using three categories of GOF activity, including 1) interference with p73 activity, 2) transactivation of genes repressed by wild-type p53, and 3) cooperation with oncogenes for transformation of rat embryonic fibroblast or mouse embryonic fibroblast cells, 103 mutp53 proteins were evaluated [20].”
BackgroundMethodNatan, E., Baloğlu, Ç., Pagel, K., Freund, S. M. V., Morgner, N., Robinson, C. V., Fersht, A. R., & Joerger, A. C. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.03.047 · Cited by 99
Sialic Acid Metabolism: A Key Player in Breast Cancer Metastasis Revealed by Metabolomics
Teoh, S. T., Ogrodzinski, M. P., Ross, C. R., Hunter, K. W., & Lunt, S. Y. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00174 · Cited by 100
“org May 2018 | Volume 8 | Article 174 Metastatic progression was originally thought to depend on clonal evolution—often accelerated by high mutation rates in cancer cells (23)—and the subsequent acquisition of prometastatic traits by a small subpopulation of cells within the primary tumor (24).”
Backgroundp53 in neurodegenerative diseases and brain cancers
Checler, F., & da Costa, C. A. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.11.009 · Cited by 99
“…effectors of gliomas rapidly converged to the demonstration of a key role for p53 in their etiology. p53 is the most frequentlymutated gene product in human cancers and especially in nervous system-associated cancers as indicated by the recently released IARC p53 database (Petitjean et al., 2007).”
Serizawa, R., Ralfkiær, U., Steven, K. E., Lam, G. W., Schmiedel, S., Schüz, J., Hansen, A., Horn, T. D., & Guldberg, P. (2010) · International Journal of Cancer · doi:10.1002/ijc.25651 · Cited by 97
“Both of these mutations have been described in Li-Fraumeni families.(34) Apart from these highly unexpected findings, no mutations or hypermethylation events were detected in urine samples from the 33 control patients.”
BackgroundPita, J. M. G., Figueiredo, I., Moura, M. M., Leite, V. A. P. H., & Cavaco, B. M. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1512 · Cited by 103
FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer
Liu, C., Barger, C. J., & Karpf, A. R. (2021) · Cancers · doi:10.3390/cancers13123065 · Cited by 99
“Moreover, GOF p53R273H and p53R248W/Q, which are three of the most common p53 mutations in ovarian cancer [130,131], were noted to dramatically increase FOXM1 protein expression in murine oviductal epithelial cells [135] and human EOC cell lines [136].”
BackgroundCell-type, Dose, and Mutation-type Specificity Dictate Mutant p53 Functions In Vivo
Lee, M. K., Teoh, W. W., Phang, B. H., Tong, W., Wang, Z. Q., & Sabapathy, K. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.022 · Cited by 104
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“number of 2916 cases, and the mutation spectrum of TP53 gene was similar to that reported previously.(27) The overall survival was compared between patient groups with different”
ResultPascual, M., Mena‐Varas, M., Robles, E. F., Garcia-Barchino, M. J., Panizo, C., Hervás‐Stubbs, S., Alignani, D., Sagardoy, A., Martínez‐Ferrandis, J. I., Bunting, K. L., et al. (2019) · Blood · doi:10.1182/blood.2018889931 · Cited by 97
Molecular genetics of testicular germ cell tumors.
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Baud, M. G. J., Bauer, M. R., Verduci, L., Dingler, F. A., Patel, K. J., Roy, D. H., Joerger, A. C., & Fersht, A. R. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.04.035 · Cited by 97
Do Mutations Turn p53 into an Oncogene?
Pitolli, C., Wang, Y., Mancini, M., Shi, Y., Melino, G., & Amelio, I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246241 · Cited by 97
“Interestingly, bone and soft-tissue sarcoma, whose incidence is very high in Le-Fraumeni patients [96], has been suggested to arise from defective mesenchymal stem cells (MSCs) [97,98].”
BackgroundTranscriptional Regulation of Estrogen Receptor-α by p53 in Human Breast Cancer Cells
Shirley, S. H., Rundhaug, J. E., Tian, J., Cullinan-Ammann, N., Lambertz, I. U., Conti, C. J., & Fuchs‐Young, R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3628 · Cited by 95
Tandon, S., Smith, C. T., Riley, R. D., Boyd, M. T., & Jones, T. M. (2010) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-09-0981 · Cited by 95
“idemiol Biomarkers Prev; 19(2) February 2010 the p53 gene (TP53) found in over 50% of cancers (3).”
BackgroundHuang, Y., Liu, N., Liu, J., Liu, Y., Zhang, C., Long, S., Luo, G., Zhang, L., & Zhang, Y. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1688951 · Cited by 94
“Those data showed that CRC patients had a high missense mutation, mainly situated within the DNAbinding domain (amino acids 102–292) [34], especially in amino acids 175 and 273 (Figure 1(a)).”
BackgroundPlexin-B1 mutations in prostate cancer
Wong, O. G., Nitkunan, T., Oinuma, I., Zhou, C., Blanc, V., Brown, R. S. D., Bott, S., Nariculam, J., Box, G., Munson, P., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702544104 · Cited by 94
Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing
Rana, H. Q., Gelman, R. S., LaDuca, H., McFarland, R. E., Dalton, E., Thompson, J. D., Speare, V., Dolinsky, J. S., Chao, E., & Garber, J. E. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy001 · Cited by 96
“Functional assays have begun to address challenges in interpreting the implications of missense alterations, which will reduce the chances of misclassification in future studies (12,36,37).”
BackgroundTu, C., Zeng, Z., Qi, P., Li, X., Guo, C. J., Xiong, F., Xiang, B., Zhou, M., Liao, Q., Yu, J., et al. (2018) · Carcinogenesis · doi:10.1093/carcin/bgy108 · Cited by 94
“TP53 is the most frequently mutated gene in other types of tumor (41); however, earlier studies have reported only infrequent or relatively low frequencies of TP53 mutations in NPC (11,13,15).”
BackgroundTindall, E. A., Petersen, D. C., Woodbridge, P., Schipany, K., & Hayes, V. M. (2009) · Human Mutation · doi:10.1002/humu.20919 · Cited by 92
“Many of the DNA variants within gene regions assessed in this study have the potential to influence susceptibility and/or progression of disease [Aoki et al., 2005; Cicek et al., 2006; Hayes and Gardiner-Garden, 2003; Petitjean et al., 2007; Rodriguez Ortner et al., 2006; Skibola et al., 2005; Wang et al., 2008], and…”
BackgroundMutant p53: One, No One, and One Hundred Thousand
Walerych, D., Lisek, K., & Sal, G. D. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00289 · Cited by 95
“The low number of such studies and the fact that other mutant p53 reactivating compounds target various mutant p53 variants may suggest that the classic distinction of contact and structural p53 mutants may not be decisive and these mutant types may, in fact, represent structural extremes of a spectrum of distortions…”
BackgroundInfluentialThe Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer
Brachova, P., Thiel, K. W., & Leslie, K. K. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140919257 · Cited by 92
Mouchawar, J., Korch, C. T., Byers, T., Pitts, T. M., Li, E., McCredie, M. R. E., Giles, G. G., Hopper, J. L., & Southey, M. C. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-0851 · Cited by 92
“The consequences of any sequence differences in the DNA samples were characterized by comparing deduced effects on coding and splicing with those documented effects in the IARC database (20, 21).”
MethodHuman cancer databases (Review)
Pavlopoulou, A., Spandidos, D. A., & Michalopoulos, I. (2014) · Oncology Reports · doi:10.3892/or.2014.3579 · Cited by 97
“the International Agency for research on cancer (IArc) tp53 (44,45) is a comprehensive resource that compiles all tp53 gene variations in human cancers derived from scientific publications.”
BackgroundLeroy, B., Ballinger, M. L., Baran‐Marszak, F., Bond, G. L., Braithwaite, A. W., Concin, N., Donehower, L. A., El‐Deiry, W. S., Fenaux, P., Gaïdano, G., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2179 · Cited by 95
Self-citationPrognostic Significance of Truncating TP53 Mutations in Head and Neck Squamous Cell Carcinoma
der Plas, M. L.-V., Brakenhoff, R. H., Kuik, D. J., Buijze, M., Bloemena, E., Snijders, P. J. F., Leemans, C. R., & Braakhuis, B. J. M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0183 · Cited by 93
Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum
Ali, A., Farrand, L., Kim, J. Y., Byun, S., Suh, J., Lee, H. J., & Tsang, B. K. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06734.x · Cited by 90
Murrow, L. M., Garimella, S. V., Jones, T. L., Caplen, N. J., & Lipkowitz, S. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0571-2 · Cited by 90
“MCF7, MB453, BT20, and ZR75 have wild-type TP53 [6, 31].”
InfluentialCannistraro, V. J., & Taylor, J. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.07.048 · Cited by 91
“Of 86 C→T mutations at eight methylated CCG and three TCG sites in non-XP squamous and basal skin cancers, 81 (97%) were at CCG sites (Table 3).(51) The lower than expected frequency of TCG→TTG mutations can be explained, in part, by the very low frequency observed for this mutation at two of the these three TCG sites…”
BackgroundClinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers
Tuna, M., Ju, Z., Yoshihara, K., Amos, C. I., Tanyi, J. L., & Mills, G. B. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0654-8 · Cited by 95
Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?Preprint
da Costa, D. C. F., de Oliveira, G. A. P., Cino, E. A., Soares, I. N., Rangel, L. P., & Silva, J. L. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023614 · Cited by 89
“Biallelic substitutions are very common in tumor-suppressor genes, but TP53 is most commonly affected by monoallelic alterations, including at six hotspots within the DNA-binding domain (R175, G245, R248, R249, R273, and R282).”
Backgroundp53, a translational regulator: contribution to its tumour-suppressor activity
Marcel, V., Catez, F., & Diaz, J. (2015) · Oncogene · doi:10.1038/onc.2015.25 · Cited by 94
Yurgelun, M. B. B., Masciari, S., Joshi, V. A., Mercado, R. C., Lindor, N. M., Gallinger, S., Hopper, J. L., Jenkins, M. A., Buchanan, D. D., Newcomb, P. A., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2015.0197 · Cited by 88
Development and translational imaging of a TP53 porcine tumorigenesis model
Sieren, J. C., Meyerholz, D. K., Wang, X., Davis, B. T., Newell, J. D., Hammond, E., Rohret, J. A., Rohret, F., Struzynski, J. T., Goeken, J. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75447 · Cited by 88
Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy
Ding, X., Zhu, Q.-G., Zhang, S., Guan, L., Li, T., Zhang, L., Wang, S., Ren, W., Chen, X.-M., Zhao, J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.18382 · Cited by 88
“Somatic mutations of TP53 gene also are different in most tumors due to the heterogeneity of HCC samples [31].”
BackgroundYoshimura, M., Ishizawa, J., Ruvolo, V. R., Dilip, A., Quintás‐Cardama, A., McDonnell, T. J., Neelapu, S. S., Kwak, L. W., Shacham, S., Kauffman, M. G., et al. (2014) · Cancer Science · doi:10.1111/cas.12430 · Cited by 90
Tornesello, M. L., Buonaguro, L., Izzo, F., & Buonaguro, F. M. (2016) · Oncotarget · doi:10.18632/oncotarget.7837 · Cited by 89
Brachova, P., Mueting, S. R., Carlson, M. J., Goodheart, M. J., Button, A. M., Mott, S. L., Dai, D. D., Thiel, K. W., Devor, E. J., & Leslie, K. K. (2014) · International Journal of Oncology · doi:10.3892/ijo.2014.2747 · Cited by 87
Genome guardian p53 and viral infections
Sato, Y., & Tsurumi, T. (2012) · Reviews in Medical Virology · doi:10.1002/rmv.1738 · Cited by 90
“Indeed, p53 is mutated or lost in over 50% of human cancers [12], representing the most commonly mutated gene in human tumors.”
BackgroundRegulation of Mutant p53 Protein Expression
Vijayakumaran, R., Tan, K. H., Miranda, P. J., Haupt, S., & Haupt, Y. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00284 · Cited by 87
“Abrogating p53 function is a key event in human cancer, leading to deregulated cell cycle, genomic instability, resistance to stress signals, and ultimately leading to cancer development (1, 2).”
BackgroundInfluentialTrbušek, M., Šmardová, J., Malčíková, J., Šebejová, L., Dobes, P., Svitáková, M., Vranová, V., Mráz, M., Francová, H. S., Doubek, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.34.7872 · Cited by 86
Osman, A. A., Neskey, D. M., Katsonis, P., Patel, A. A., Ward, A. M., Hsu, T., Hicks, S. C., McDonald, T. O., Ow, T. J., Alves, M. V. O., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2729 · Cited by 86
“The percentage of patients with wtp53, 62%, is higher than expected, which could be attributed to either the sensitivity of sequencing TP53 from paraffin tissues or sequencing exons 5–8, as only approximately 80% of mutations occur within the DNA-binding domain (36).”
Gordo, S., Martos, V., Santos, E., Menéndez, M., Bó, C., Giralt, E., & de Mendoza, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805658105 · Cited by 86
P53-R273H mutation enhances colorectal cancer stemness through regulating specific lncRNAs
Zhao, Y., Li, Y., Sheng, J., Wu, F., Li, K., Huang, R. S., Wang, X., Jiao, T., Guan, X., Lu, Y., et al. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1375-9 · Cited by 85
“Among single allele mutant types, there are three ‘hot-spot’ mutations that are categorized into the following two types: conformational mutations, such as R175H; and DNA-contact mutations represented by R248W and R273H [6].”
InfluentialBoultwood, J., Perry, J., Zaman, R., Fernandez-Santamaria, C., Littlewood, T. J., Kušec, R., Pellagatti, A., Wang, L., Clark, R. E., & Wainscoat, J. S. (2010) · Leukemia · doi:10.1038/leu.2010.65 · Cited by 85
Targeting Therapies for the p53 Protein in Cancer Treatments
Levine, A. J. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055455 · Cited by 84
Towards an understanding of the role of p53 in adrenocortical carcinogenesis
Wasserman, J. D., Zambetti, G. P., & Malkin, D. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.09.010 · Cited by 84
“Nevertheless, ACC constitutes the plurality of tumors identified in carriers of the R337H allele (Petitjean et al., 2007b).”
Guedes, L. B., Almutairi, F., Haffner, M. C., Rajoria, G., Liu, Z., Klimek, S., Zoino, R., Yousefi, K., Sharma, R. B., Marzo, A. M. D., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0257 · Cited by 87
Leslie, K. K., Filiaci, V. L., Mallen, A. R., Thiel, K. W., Devor, E. J., Moxley, K. M., Richardson, D. L., Mutch, D. G., Secord, A. A., Tewari, K. S., et al. (2021) · Gynecologic Oncology · doi:10.1016/j.ygyno.2021.01.025 · Cited by 84
“[4] Reflective of previous studies from multiple tumor sites,[19] the majority of mutations in TP53 occurred in the DNA binding domain of the gene (Figure 1).”
BackgroundAssociation of T P53 and CDKN2A Mutation Profile with Tumor Mutation Burden in Head and Neck Cancer
Deneka, A. Y., Baca, Y., Serebriiskii, I. G., Nicolas, É., Parker, M. I., Nguyen, T. T., Xiu, J., Korn, W. M., Demeure, M. J., Wise-Draper, T. M., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-4316 · Cited by 91
The role of SOG1, a plant-specific transcriptional regulator, in the DNA damage response
Yoshiyama, K., Kimura, S., Maki, H., Britt, A., & Umeda, M. (2014) · Plant Signaling & Behavior · doi:10.4161/psb.28889 · Cited by 86
“The importance of the role of p53 in maintaining genome stability is exemplified by the finding that this molecule is mutated in more than 50% of human cancers.(32) p53 is present at low levels under unperturbed conditions, but after exposure to DNA-damaging agents it is stabilized by post-translational modifications,…”
BackgroundEMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours
Bornachea, O., Santos, M., Martínez‐Cruz, A. B., García‐Escudero, R., Dueñas, M., Costa, C., Segrelles, C., Lorz, C., Buitrago, A., Sáiz-Ladera, C., et al. (2012) · Scientific Reports · doi:10.1038/srep00434 · Cited by 84
Fitzgerald, A. L., Osman, A. A., Xie, T.-X., Patel, A. A., Skinner, H., Sandulache, V. C., & Myers, J. N. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.44 · Cited by 84
Cheng, L. L., Itahana, Y., Lei, Z. D., Chia, N., Wu, Y., Yu, Y., Zhang, S. L., Thike, A. A., Pandey, A., Rozen, S., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0036 · Cited by 89
“AllTP53mutations in the gastric cancer cells found were inactivating (28).”
Walerych, D., Olszewski, M. B., Gutkowska, M., Helwak, A., Żylicz, M., & Żylicz, M. (2009) · Oncogene · doi:10.1038/onc.2009.281 · Cited by 82
“Oncogenic mutations of TP53 gene, detected in over 50% of various human tumors, are mostly localized in the region encoding p53 DBD (Petitjean et al., 2007), and are known to cause additional destabilization of its structure (‘structural mutants’) and/or directly disrupt its DNA contact (‘contact mutants’) (Cho et al.”
BackgroundMutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes
Simeonova, I., Jaber, S., Drašković, I., Bardot, B., Fang, M., Bouarich-Bourimi, R., Lejour, V., Charbonnier, L., Soudais, C., Bourdon, J., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.05.028 · Cited by 92
Jasek, M., Gondek, L. P., Bejanyan, N., Tiu, R. V., Huh, J. Y., Theil, K. S., O'Keefe, C., McDevitt, M. A., & Maciejewski, J. P. (2009) · Leukemia · doi:10.1038/leu.2009.189 · Cited by 83
Avery‐Kiejda, K. A., Morten, B. C., Wong‐Brown, M. W., Mathe, A., & Scott, R. J. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt411 · Cited by 83
“Furthermore, it may offer some explanation for the discrepancies between p53 mutation status and prognosis in the literature (36).”
BackgroundResultNedelko, T., Arlt, V. M., Phillips, D. H., & Hollstein, M. C. (2008) · International Journal of Cancer · doi:10.1002/ijc.24006 · Cited by 82
“–2The TP53 functional status of cells with a given mutation refers to transcriptional transactivation function in the yeast assay as defined in Petitjean et al.12 and tabulated in the IARC TP53 database (http://www-p53.iarc.fr): NF, non-functional; PF, partially functional; F, functional (wild-type activity).”
BackgroundMethodNPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse
Höllein, A., Meggendorfer, M., Dicker, F., Jeromin, S., Nadarajah, N., Kern, W., Haferlach, C., & Haferlach, T. (2018) · Blood Advances · doi:10.1182/bloodadvances.2018023432 · Cited by 84
Hofstetter, G., Berger, A., Fiegl, H., Slade, N., Zorić, A., Holzer, B., Schuster, E., Möbus, V. J., Reimer, D., Daxenbichler, G., et al. (2010) · Oncogene · doi:10.1038/onc.2009.482 · Cited by 82
“Compared to previous studies in ovarian cancer tissue, we found a relatively high percentage of cancer cell lines exhibiting functionally inactive p53 (IARC TP53 Mutation Database, version R13, November 2008; Petitjean et al., 2007).”
ResultHouben, R., Dreher, C., Angermeyer, S., Borst, A., Utikal, J. S., Haferkamp, S., Peitsch, W. K., Schrama, D., & Hesbacher, S. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.169 · Cited by 88
Fundamental immune–oncogenicity trade-offs define driver mutation fitness
Hoyos, D., Zappasodi, R., Schulze, I., Sethna, Z. M., de Andrade, K. C., Bajorin, D. F., Bandlamudi, C., Callahan, M. K., Funt, S. A., Hadrup, S. R., et al. (2022) · Nature · doi:10.1038/s41586-022-04696-z · Cited by 81
Exploring background mutational processes to decipher cancer genetic heterogeneity
Goncearenco, A., Rager, S. L., Li, M., Sang, Q. A., Rogozin, I. B., & Panchenko, A. R. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx367 · Cited by 76
“There is experimental evidence (47) that any missense mutations in codons of DNA-binding arginine result in a loss of function, whereas many amino acid substitutions of another arginine can be tolerated (48).”
BackgroundReviving the guardian of the genome: Small molecule activators of p53
Nguyen, D., Liao, W., Zeng, S. X., & Lu, H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.03.013 · Cited by 84
Boyault, S., Drouet, Y., Navarro, C., Bachelot, T., Lasset, C., Treilleux, I., Tabone, É., Puisieux, A., & Wang, Q. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-011-1518-y · Cited by 85
Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy
Li, J., Yang, L., Gaur, S., Zhang, K., Wu, X., Yuan, Y., Li, H., Hu, S., Weng, Y., & Yen, Y. (2014) · Human Mutation · doi:10.1002/humu.22528 · Cited by 80
“R273G (R273G) has also been reported to occur at a low rate in breast and lung cancers [Petitjean et al., 2007].”
BackgroundInfluentialUSP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells
Padmanabhan, A., Candelaria, N., Wong, K.-K., Nikolai, B. C., Lonard, D. M., O’Malley, B. W., & Richards, J. S. (2018) · Nature Communications · doi:10.1038/s41467-018-03599-w · Cited by 88
Li, J., Meeks, H., Feng, B., Healey, S. C., Thorne, H., Makunin, I. V., Ellis, J. J., kConFab Investigators, Campbell, I., Southey, M. C., et al. (2015) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103452 · Cited by 82
Metadata
- Authors
- Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S. V., Hainaut, P., & Olivier, M.
- Affiliations
- Centre international de recherche sur le cancer (FR)
- Tohoku University (JP)
- World Health Organization (CH)
- Corresponding author
- Hainaut, Pierre
- ORCID
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2007-06
- Volume
- 28
- Issue
- 6
- Pages
- 622-629
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- OpenAlex
- W1986076152
- Cited by
- 1,598
- References
- 26
- Citations by year
- 2026: 24 · 2025: 36 · 2024: 34 · 2023: 42 · 2022: 59 · 2021: 87 · 2020: 68 · 2019: 81 · 2018: 75 · 2017: 83 · 2016: 120 · 2015: 135 · 2014: 136 · 2013: 131 · 2012: 143
- FWCI
- 41.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 3014 d)
- Locations
- Human Mutation (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- TP53, TP53 mutation, missense mutations, mutational hotspots, dominant negative effect, tumor suppressor, nucleotide substitution rates, mutation patterns, tumor phenotype
- MeSH terms
- DNA Mutational Analysis, Humans, Mutation, Neoplasms, Phenotype, Transcriptional Activation, Tumor Suppressor Protein p53, Age of Onset, Germ-Line Mutation, Databases, Genetic
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