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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]
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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].”
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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
Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., & Jacks, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.004 · Cited by 1,308 · cited 1×
“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].”
BackgroundSelf-citationThe clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.
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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Items 601–700 of 999
Cho, E. J., Kim, M., Jo, D., Kim, J., Oh, J., Chung, H. C., Lee, S.-H., Kim, D., Chun, S., Kim, J., et al. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02034-1 · Cited by 36
“, 1) interference with p73 activity, 2) transactivation of genes downregulated by wild-type p53, and 3) cooperation with oncogenes during transformation of rat or mouse embryonic fibroblasts [41].”
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“In fact, 25% of all somatic mutations in the p53 tumor suppressor gene in human tumors involve C to T transitions at CpG, and, in some tumors, this figure rises to almost 50% (5).”
Dominant Effects of Δ40p53 on p53 Function and Melanoma Cell Fate
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“The importance of proper p53 function is emphasized by its high mutation frequency among human cancers (Hollstein et al., 1991; Levine et al., 1991; Petitjean et al., 2007) and the overexpression of ‘mutant’ p53 in certain tumors suggests that some mutations may have a dominant-negative effect on wildtype p53 (Goldste…”
BackgroundPrevalence of human papillomavirus 16/18/33 infection and p53 mutation in lung adenocarcinoma
Iwakawa, R., Kohno, T., Enari, M., Kiyono, T., & Yokota, J. (2010) · Cancer Science · doi:10.1111/j.1349-7006.2010.01622.x · Cited by 36
Simões, M. L., Hockley, S. L., Schwerdtle, T., da Costa, G. G., Schmeiser, H. H., Phillips, D. H., & Arlt, V. M. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.06.006 · Cited by 36
“The importance of this protein is highlighted by the fact that it is mutated in 50% of human tumours (Petitjean et al., 2007).”
Unraveling the Role of Huntingtin in Breast Cancer Metastasis
Thion, M. S., McGuire, J. R., Sousa, C. M., Fuhrmann, L., Fitamant, J., Leboucher, S., Vacher, S., du Montcel, S. T., Bièche, I., Bernet, A., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv208 · Cited by 35
“P53 is most frequently found mutated in basal breast carcinomas (32,35), suggesting that it may participate in the decreased HTT expression found in this subtype.”
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“E17D and K24N are frequently associated with female genital cancers [33]; D49Y and W53G are predicted to cause the largest changes in the disorder tendency based on metaPrDOS sequence analysis [90] and are associated with brain and bladder cancers, respectively [91,92]; and N29K/N30D is only complex cancer mutant know…”
BackgroundMethodInfluentialIkezoe, T., Yang, J., Nishioka, C., & Yokoyama, A. (2009) · International Journal of Hematology · doi:10.1007/s12185-009-0462-7 · Cited by 35
Braakhuis, B. J. M., Rietbergen, M. M., Buijze, M., Snijders, P. J. F., Bloemena, E., Brakenhoff, R. H., & Leemans, C. R. (2013) · Oral Diseases · doi:10.1111/odi.12178 · Cited by 35
Rárová, L., Steigerová, J., Kvasnica, M., Bartůněk, P., Křížová, K., Chodounská, H., Kolář, Z., Sedlák, D., Oklešťková, J., & Strnad, M. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.017 · Cited by 35
“The p53 gene also plays a crucial role in cell cycle regulation [89].”
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“Within this domain are several mutations at K120 that have been documented in human cancer, including K120R, K120E, K120M, K120N and K120Q (Petitjean et al., 2007).”
BackgroundStiasny, A., Freier, C. P., Kühn, C., Schulze, S., Mayr, D. C., Alexiou, C., Janko, C., Wiest, I., Dannecker, C., Jeschke, U., et al. (2017) · Oncology Letters · doi:10.3892/ol.2017.6752 · Cited by 37
“In contrast, only 45% of the less frequent mutants studied have this capacity (36).”
Makino, E., Gutmann, V., Kosnopfel, C., Niessner, H., Forschner, A., Garbe, C., Sinnberg, T. W., & Schittek, B. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0952-8 · Cited by 35
Hernández‐Reséndiz, I., Gallardo‐Pérez, J. C., López-Macay, Á., Robledo‐Cadena, D. X., García-Villa, E., Gariglio, P., Saavedra, E., Moreno‐Sánchez, R., & Rodríguez‐Enríquez, S. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27354 · Cited by 36
Comprehensive analysis of regulation of DNA methyltransferase isoforms in human breast tumors
Hegde, M., & Joshi, M. B. (2021) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-021-03519-4 · Cited by 37
Smirnov, E., Chmúrčiaková, N., & Cmarko, D. (2021) · Cells · doi:10.3390/cells10123452 · Cited by 37
Inhibition of p53 protein aggregation as a cancer treatment strategy
Kwan, K., Castro-Sandoval, O., Gaiddon, C., & Storr, T. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2022.102230 · Cited by 35
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“fr, R17) [23], these point mutations result in missense substitutions Ala to Val or Arg to Trp, respectively.”
BackgroundDebelenko, L. V., Pérez‐Atayde, A. R., DuBois, S. G., Grier, H. E., Pai, S., Shamberger, R. C., & Kozakewich, H. P. (2009) · Pediatric and Developmental Pathology · doi:10.2350/09-08-0694-oa.1 · Cited by 35
“4Present address: Department of Pathology, St. Jude Children’s Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA *Corresponding author, e-mail: larisa.debelenko@stjude.org listed among the 138 soft tissue sarcomas in patients with germline p53 mutations in the International Agency for Research on Cancer (IARC)…”
BackgroundMethodInfluentialThree-dimensional modeling of the human fallopian tube fimbriae
Eddie, S. L., Quartuccio, S. M., Zhu, J., Shepherd, J. A., Kothari, R., Kim, J. J., Woodruff, T. K., & Burdette, J. E. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.12.015 · Cited by 35
“This is counter to the majority of p53 alterations seen in HGSC, where mutation allows for p53 gain-of-function rather than silencing [11].”
BackgroundStattin, E., Boström, I. M., Winbo, A., Cederquist, K., Jonasson, J., Jonsson, B., Diamant, U., Jensen, S. M., Rydberg, A., & Norberg, A. (2012) · BMC Cardiovascular Disorders · doi:10.1186/1471-2261-12-95 · Cited by 35
“The Alamut software assists in evaluation of missense variants by compiling output from a number of bioinformatic prediction tools, including Polymorphism Phenotyping (PolyPhen), Sorting Intolerant From Tolerant (SIFT) and Align Grantham Variation and Grantham Deviation (Align-GVGD) [22-24].”
MethodShi, H., Lambert, J. M. R., Hautefeuille, A. H., Bykov, V. J. N., Wiman, K. G., Hainaut, P. L., & de Fromentel, C. C. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm266 · Cited by 35
“Many of these mutations are missense and lead to the synthesis of structurally altered proteins that have lost their transactivation activity due to single amino acid changes, resulting in impaired tumoursuppressing function ( 14 ).”
BackgroundSelf-citationNoon, A. P., Polański, R., Elfert, A. Y., Kalirai, H., Shawki, H., Campbell, F., Dodson, A., Eccles, R. M., Lloyd, B. H., Sibson, D. R., et al. (2011) · British Journal of Urology · doi:10.1111/j.1464-410x.2011.10433.x · Cited by 34
Salaverría, I., Martín‐Guerrero, I., Burkhardt, B., Kreuz, M., Zenz, T., Oschlies, I., Arnold, N., Baudis, M., Bens, S., García‐Orad, Á., et al. (2012) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22014 · Cited by 35
“consequences in silico were determined according to the IARC TP53 Database (R15) (Petitjean et al., 2007).”
MethodDeleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan
Rashid, M. U., Muhammad, N., Faisal, S., Amin, A., & Hamann, U. (2014) · Breast Cancer Research and Treatment · doi:10.1007/s10549-014-2972-0 · Cited by 35
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“p53 is the most frequent target for mutation in tumors, occurring predominantly as missense mutations, several of which occur as “hot spot” mutations in the DNA-binding core domain [1].”
Recognition of Local DNA Structures by p53 Protein
Brázda, V., & Coufal, J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020375 · Cited by 41
“The vertical bars indicate the relative missense-mutation frequency in human cancer for each residue (Tp53 Mutation Database [69].”
BackgroundCancer-related Mutations with Local or Long-range Effects on an Allosteric Loop of p53
Degn, K., Beltrame, L., Hede, F. D., Sora, V., Nicolaci, V., Vabistsevits, M., Schmiegelow, K., Wadt, K., Tiberti, M., Lambrughi, M., et al. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167663 · Cited by 28
The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome
Lamprecht, B., Kreher, S., Möbs, M., Sterry, W., Dörken, B., Janz, M., Assaf, C., & Mathas, S. (2012) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2012.10918.x · Cited by 34
Kojima, K., Konopleva, M. Y., Tsao, T., Andreeff, M., Ishida, H., Shiotsu, Y., Jin, L., Tabe, Y., & Nakakuma, H. (2009) · Leukemia · doi:10.1038/leu.2009.212 · Cited by 33
Coffill, C. R., Lee, A., Siau, J. W., Chee, S. M. Q., Joseph, T. L., Tan, Y. S., Madhumalar, A., Tay, B.-H., Brenner, S., Verma, C. S., et al. (2016) · Genes & Development · doi:10.1101/gad.274118.115 · Cited by 34
“More than 50% of all human cancers contain mutations in the p53 tumor suppressor protein (Petitjean et al. 2007).”
Thaler, S., Thiede, G., Hengstler, J. G., Schad, A., Schmidt, M., & Sleeman, J. P. (2014) · International Journal of Cancer · doi:10.1002/ijc.29404 · Cited by 34
Wild-type and Hupki (Human p53 Knock-in) Murine Embryonic Fibroblasts
Whibley, C. E., Odell, A. F., Nedelko, T., Balaburski, G. M., Murphy, M. E., Liu, Z., Stevens, L., Walker, J. H., Routledge, M. N., & Hollstein, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.064444 · Cited by 33
Predicting survival in head and neck squamous cell carcinoma from TP53 mutation
Masica, D. L., Li, S., Douville, C. B., Manola, J. B., Ferris, R. L., Burtness, B. A., Forastiere, A. A., Koch, W. M., Chung, C. H., & Karchin, R. (2014) · Human Genetics · doi:10.1007/s00439-014-1470-0 · Cited by 33
Ehrhardt, H., Schrembs, D., Moritz, C., Wachter, F., Haldar, S., Graubner, U. B., Nathrath, M., & Jeremias, I. (2011) · Blood · doi:10.1182/blood-2010-02-269811 · Cited by 33
p53-R273H upregulates neuropilin-2 to promote cell mobility and tumor metastasis
Lv, T., Wu, X., Sun, L., Hu, Q., Wan, Y., Wang, L., Zhao, Z., Tu, X., & Xiao, Z. J. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.376 · Cited by 33
“It is well documented that hotspot mutations of p53 gene, in particular, R175H, R248W and R273H, are loss of function alleles as they are unable to transactivate downstream genes involved cell growth control and apoptosis.(24) However, it becomes clear that these mutant alleles, in addition, exhibit gain of new functi…”
BackgroundMetabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
Allende-Vega, N., & Villalba, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-42220-y · Cited by 32
FBXL6 degrades phosphorylated p53 to promote tumor growth
Li, Y., Cui, K., Zhang, Q., Lin, X., Lin, X., Tang, Y., Prochownik, E. V., & Li, Y. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00739-6 · Cited by 34
Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics
Phan, T. T. T., Lin, Y., Chou, Y., Wu, C., & Lin, L. (2022) · Oncogenesis · doi:10.1038/s41389-022-00401-x · Cited by 34
Zhao, Y., Zhang, Y., Yang, Z., Li, A., & Dong, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.03.148 · Cited by 31
“Given the critical role of p53 in apoptosis, we performed sequencing analysis of p53 cDNA and found that 624Mel cells harbor a T1076G (Cys275Trp) mutation in the DNA binding domain that is likely to compromise the transcription and apoptosis function of p53 (Petitjean et al., 2007), suggesting that the observed apopto…”
BackgroundMethodLow-level p53 expression changes transactivation rules and reveals superactivating sequences
Jordan, J. J., Menéndez, D., Sharav, J., Beno, I., Rosenthal, K., Resnick, M. A., & Haran, T. E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205971109 · Cited by 33
“GGA (Con5) cGGACATGTCCGGACATGTCCtg 175 (18) 36 (4) 23 (1) ** GGA + 2 nt cGGACATGTCCgcGGACATGTCCtg 188 (17) 101 (9) 3.”
TP53 Mutation Analysis in Clinical Practice: Lessons From Chronic Lymphocytic Leukemia
Malčíková, J., Pavlová, Š., Kozubík, K. S., & Pospı́šilová, Š. (2014) · Human Mutation · doi:10.1002/humu.22508 · Cited by 33
“Similar data may also be observed for CLL in the IARC TP53 Database (R16, November 2012) [Petitjean et al., 2007], where the G>A versus C>T ratio is even higher 2.45:1, whereas other cancers showed a closer ratio (e.g., breast and colon cancer 1.4:1).”
ResultInfluentialBuckley, N. E., D’Costa, Z., Kaminska, M., & Mullan, P. B. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.31 · Cited by 33
“Up to 40% of human cancers express high levels of mutant p53 and 74% of these are missense mutations that fall within its central DNAbinding domain.(26) Using both zebrafish and mouse models, studies have shown that mutation alone is not sufficient to confer stability to the protein in the absence of stress.”
BackgroundStructural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode
Vainer, R., Cohen, S., Shahar, A., Zarivach, R., & Arbely, E. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.06.009 · Cited by 33
Semenzati, G. D. O., Salgado, B. S., Rocha, N. S., Matheus, S. M. M., de Carvalho, L. R., & Martins, R. H. G. (2012) · Inhalation Toxicology · doi:10.3109/08958378.2012.715317 · Cited by 32
“Alterations in the TP53 gene are found in 42% of head and neck squamous carcinomas, 60% of laryngeal tumours, and 37% of hypopharyngeal tumors (Maestro et al., 1992; Frank et al., 1994; Brennan et al., 1995; Olshan et al., 1997; Petitjean et al., 2007).”
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RNF38 encodes a nuclear ubiquitin protein ligase that modifies p53
Sheren, J. E., & Kassenbrock, C. K. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.08.031 · Cited by 32
“The p53 tumor suppressor gene (TP53) has been termed “the guardian of the genome” [1] and it is one of the most frequently mutated genes in human cancers [2, 3, 4, 5].”
BackgroundTumor Suppressors Status in Cancer Cell Line Encyclopedia
Sonkin, D., Hassan, M., Murphy, D. J., & Tatarinova, T. V. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.04.001 · Cited by 32
“Not surprisingly, TP53 is inactivated in about 50% cases by dominant negative mutations (Petitjean et al., 2007).”
BackgroundNing, Y., Hui, N., Qing, B., Zhuo, Y., Sun, W., Du, Y., Liu, S., Liu, K., & Zhou, J. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1635-9 · Cited by 33
Xie, T., Zhou, G., Zhao, M., Sano, D., Jasser, S. A., Brennan, R. G., & Myers, J. N. (2013) · The Laryngoscope · doi:10.1002/lary.23846 · Cited by 31
Mutant p53 exerts oncogenic effects through microRNAs and their target gene networks
Li, X. L., Jones, M. F., Subramanian, M., & Lal, A. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.03.054 · Cited by 33
“1, is the most frequently mutated gene in human cancer with more than 50% of all tumors exhibiting mutation at this locus [37,38].”
Discovery of novel tumor suppressor p53 response elements using information theory
Lyakhov, I. G., Krishnamachari, A., & Schneider, T. D. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn189 · Cited by 32
Molecular dynamics of the full-length p53 monomer
Chillemi, G., Davidovich, P. B., D’Abramo, M., Mametnabiev, T. E., Garabadzhiu, A. V., Desideri, A., & Melino, G. (2013) · Cell Cycle · doi:10.4161/cc.26162 · Cited by 31
“The tumor suppressor protein p53 is composed of three large domains: (1) the intrinsically flexible N-terminal region, which includes 2 transactivation domain (TAD) and a proline-rich region (PRO); (2) the central core region, which contains the DNA binding domain (DBD) region with a coordinated Zn ion between β sheet…”
BackgroundMethodAdaptive Evolution of p53 Thermodynamic Stability
Khoo, K. H., Andreeva, A. E., & Fersht, A. R. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.08.013 · Cited by 32
Chen, L., Ahmad, N., & Liu, X. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1151582 · Cited by 32
“Since wild type (WT) p53 could induce apoptosis, cancer cells use different ways to inactive p53, such as downregulation of protein level or loss-of function mutations.(16-18) Despite the high rate of p53 mutations in different kinds of cancers,(19,20) some cancers do harvest WT p53.”
BackgroundTan, Y. S., Mhoumadi, Y., & Verma, C. S. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz009 · Cited by 34
Sinha, S., Dwivedi, T. R., Yengkhom, R., Bheemsetty, V. A., Abe, T., Kiyonari, H., VijayRaghavan, K., & Inamdar, M. S. (2019) · Blood · doi:10.1182/blood.2019000530 · Cited by 32
GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma
Vater, I., Wagner, F., Kreuz, M., Berger, H., Martín-Subero, J. I., Pott, C., Martinez-Climent, J. A., Klapper, W., Krause, K., Dyer, M. J. S., et al. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07443.x · Cited by 33
“Sequence variations were checked and named according to the R12 release of the IARC TP53 Database (Petitjean, et al 2007) to determine whether they are rare polymorphisms or deleterious.”
MethodChang, V. Y., Federman, N. C., Martínez-Agosto, J. A., Tatishchev, S. F., & Nelson, S. F. (2012) · Pediatric Blood & Cancer · doi:10.1002/pbc.24316 · Cited by 31
“This patient’s germline TP53 mutation involves R248W, which is the same amino acid change that has been reported in many families with LFS, including at least two individuals with GA [34].”
BackgroundBizzarri, A. R., Moscetti, I., & Cannistraro, S. (2018) · Analytica Chimica Acta · doi:10.1016/j.aca.2018.04.049 · Cited by 32
Costa, T. E. J. B., Gerber, V. K. Q., Ibañez, H. C., Melanda, V. S., Parise, I. Z. S., Watanabe, F. M., Pianovski, M. A. D., Fiori, C. M. C. M., Fabro, A. L. M. R., Silva, D. B., et al. (2019) · Cancers · doi:10.3390/cancers11111804 · Cited by 32
Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties
Garg, A., Hazra, J. P., Sannigrahi, M. K., Rakshit, S., & Sinha, S. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.12.015 · Cited by 31
An Updated Focus on Quadruplex Structures as Potential Therapeutic Targets in Cancer
Sánchez-Martín, V., López-Pujante, C., Soriano, M., & Garcia-Salcedo, J. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238900 · Cited by 31
Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner
Haupt, S., Mitchell, C., Corneille, V., Shortt, J., Fox, S. B., Pandolfi, P. P., Castillo-Martín, M., Bonal, D. M., Cordon-Carlo, C., Lozano, G., et al. (2013) · Cell Cycle · doi:10.4161/cc.24805 · Cited by 29
“Clearly it would be important to know the status of p53 in these tumors, where other studies have defined a ~30% incidence of p53 mutations in human soft tissue sarcomas.(32,40) We have addressed this in a small study on selected sarcoma types and grades and identified a subset of leiomysarcomas with Figure 3.”
BackgroundLee, M. K., & Sabapathy, K. (2008) · Journal of Cell Science · doi:10.1242/jcs.022822 · Cited by 31
“been intensely studied, mainly through analyzing the properties of the commonly found hot-spot DNA-binding-domain mutations such as R175H, G245S, R248W, R249S, R273H and R282W (Petitjean et al., 2007).”
BackgroundInfluentialWip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis
Zane, L. K., Yasunaga, J., Mitagami, Y., Yedavalli, V. R. K., Tang, S.-W., Chen, C., Ratner, L., Lu, X., & Jeang, K.-T. (2012) · Retrovirology · doi:10.1186/1742-4690-9-114 · Cited by 34
“Thus, approximately 50% of human cancers are genetically mutated in p53 [29,82-85], and the other 50% show attenuated or abrogated p53 activity through means other than mutation [86].”
BackgroundLong range recognition and selection in IDPs: the interactions of the C-terminus of p53
Kannan, S., Lane, D. P., & Verma, C. S. (2016) · Scientific Reports · doi:10.1038/srep23750 · Cited by 31
Christgen, M., Noskowicz, M., Heil, C., Schipper, E., Christgen, H., Geffers, R., Kreipe, H. H., & Lehmann, U. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.126 · Cited by 31
Gogna, R., Madan, E., Khan, M., Pati, U., & Kuppusamy, P. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201202055 · Cited by 30
“These mutants result in the lack of p53 apoptosis response (Petitjean et al, 2007).”
Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine
Fredebohm, J., Wolf, J. M., Hoheisel, J. D., & Boettcher, M. (2013) · Journal of Cell Science · doi:10.1242/jcs.124768 · Cited by 30
“BxPC-3 and MiaPaca-2 cell lines both carry deleterious mutations in the DNAbinding domain of p53 (Petitjean et al., 2007) necessary for transcriptional regulation.”
BackgroundNian, Y., Zhu, H., Tang, W., Luo, Y., Du, J., & Qiu, M. (2013) · Journal of Natural Products · doi:10.1021/np4000262 · Cited by 30
Doig, K., FELLOWES, A. P., Bell, A. H., Seleznev, A., Ma, D. K. G., Ellul, J., Li, J., Doyle, M., Thompson, E. R., Kumar, A., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0427-z · Cited by 30
“Annotated variants are cached and keyed by data source which currently includes VEP [41], Annovar [42, 43], Mutalyzer [38], Clinvitae [44] and IARC [45].”
MethodShen, T., Li, S., Wang, J., Zhang, T., Zhang, S., Chen, H., Xiao, Q., Ren, W., Liu, C., Peng, B., et al. (2020) · Liver International · doi:10.1111/liv.14581 · Cited by 31
Ma, J., Zhang, L., Chen, J., Song, B., Zang, C., & Liu, H. (2021) · BMC Bioinformatics · doi:10.1186/s12859-021-04007-9 · Cited by 30
p53: a molecular marker for the detection of cancer
Boyd, M. T., & Vlatković, N. (2008) · Expert Opinion on Medical Diagnostics · doi:10.1517/17530059.2.9.1013 · Cited by 30
“In addition, the importance of the nature/identity of the mutation in p53 is becoming increasingly apparent [101,108,109] .”
InfluentialIncreased galectin-7 gene expression in lymphoma cells is under the control of DNA methylation
Demers, M., Couillard, J., Giglia‐Mari, G., Magnaldo, T., & St‐Pierre, Y. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.07.015 · Cited by 30
p53 Binds to Estrogen Receptor 1 Promoter in Human Breast Cancer Cells
Rasti, M., Arabsolghar, R., Khatooni, Z., & Mostafavi‐Pour, Z. (2011) · Pathology & Oncology Research · doi:10.1007/s12253-011-9423-6 · Cited by 30
MIAO, W., Liu, X., Wang, H., Fan, Y., Lian, S., Yang, X., Wang, X., GUO, G., LI, Q., & WANG, S. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3255 · Cited by 30
“The mutations not only result in p53 protein loss of wild-type function, in the majority of cases, mutant p53 protein acquires an oncogenic gain of function (38-41).”
BackgroundTranscriptional control of the proliferation cluster by the tumor suppressor p53
Brosh, R., & Rotter, V. (2009) · Molecular BioSystems · doi:10.1039/b911416e · Cited by 31
Sjo, O. H., Berg, M., Merok, M. A., Kolberg, M., Svindland, A., Lothe, R. A., & Nesbakken, A. (2011) · Journal of Surgical Oncology · doi:10.1002/jso.21959 · Cited by 30
“Both the distribution of mutations within the TP53 gene and the types of mutations were similar in PC patients as compared to multicenter non-PC patients [12] as well as colon cancers in the IARC database [13].”
Resultp53 and its mutants on the slippery road from stemness to carcinogenesis
Molchadsky, A., & Rotter, V. (2017) · Carcinogenesis · doi:10.1093/carcin/bgw092 · Cited by 30
“Moreover, the effect and the degree of oncogenic GOF exhibited by the p53 mutants is dependent on the type of nucleotide substitution, specific position in the p53 gene DNA sequence and the particular cellular conditions; thus further entangling the relationship between mut-p53 genotype and phenotype (85,99,108).”
BackgroundKappel, S., Janschek, E., Wolf, B., Rudas, M., Teleky, B. K., Jakesz, R., & Kandioler, D. (2015) · Breast Cancer Research and Treatment · doi:10.1007/s10549-015-3424-1 · Cited by 30
“The IARC TP53 Database (R17, last updated November 2013) reports only seven hits for this TP53 mutation [21].”
TP53 mutations in circulating free DNA from Egyptian patients with non-Hodgkin’s lymphoma
Hosny, G., Farahat, N. M. G., & Hainaut, P. L. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.10.029 · Cited by 30
Self-citationPing, Z., Siegal, G. P., Almeida, J. S., Schnitt, S. J., & Shen, D. (2014) · Journal of Pathology Informatics · doi:10.4103/2153-3539.126147 · Cited by 28
“Wild‐type TP53 normally functions in the maintenance of genetic stability and its mutation has been proposed as being responsible for a mutator phenotype in cancer cells.[38,39] In our study, the total MC in the IDC cases with TP53 mutation was significantly higher than those without TP53 mutations.”
BackgroundBrancato, B., Munnia, A., Cellai, F., Ceni, E., Mello, T., Bianchi, S., Catarzi, S., Risso, G., Galli, A., & Peluso, M. (2016) · DNA Research · doi:10.1093/dnares/dsw018 · Cited by 29
“1) corresponding to a region of the TP53 with high mutation rates.(11) The presence of oxidative damage in the experimental cells treated with the ROS-generating system was confirmed using the (32)P-postlabelling technique.”
MethodIrimie, A. I., Braicu, C., Pileczki, V., Petrushev, B., Şoriţău, O., Câmpian, R. S., & Berindan‐Neagoe, I. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2751-9 · Cited by 29
The Role of p53/p21/p16 in DNA-Damage Signaling and DNA Repair
Kulaberoglu, Y., Gündoğdu, R., & Hergovich, A. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803309-8.00015-x · Cited by 30
Braña, I., Pham, N., Kim, L., Sakashita, S., Li, M., Ng, C., Wang, Y., Loparco, P., Sierra, R. J., Wang, L. E., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19109 · Cited by 29
“The LADC had a TP53 missense mutation causing a complete loss of function of p53 [44].”
BackgroundGenotype–phenotype associations among panel-based TP53+ subjects
Rana, H. Q., Clifford, J., Hoang, L., LaDuca, H., Black, M. H., Li, S., McGoldrick, K., Speare, V., Dolinsky, J. S., Gau, C., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0541-y · Cited by 31
Arolt, C., Meyer, M. F., Rüsseler, V., Nachtsheim, L., Wuerdemann, N., Dreyer, T., Gattenlöhner, S., Wittekindt, C., Buettner, R., Quaas, A., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02551-6 · Cited by 30
Qian, J., Zhang, W., Wei, P., Yao, G., Yi, T., Zhang, H., Ding, H., Huang, X., Wang, M., Song, Y., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202001994 · Cited by 29
The potential roles of p53 signaling reactivation in pancreatic cancer therapy
Ou, A., Zhao, X., & Lu, Z. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188662 · Cited by 30
Cheung, P. F., Yip, C. W., Ng, L. W. C., Lo, K. W., Wong, N., Choy, K. W., Chow, C., Chan, K. F., Cheung, T. T., Poon, R. T. P., et al. (2014) · Cancer Cell International · doi:10.1186/s12935-014-0103-y · Cited by 29
“most common mutations are missense mutations leading to amino acid substitutions [43-45].”
Bersani, F., Taulli, R., Accornero, P., Morotti, A., Miretti, S., Crepaldi, T., & Ponzetto, C. (2008) · European Journal of Cancer · doi:10.1016/j.ejca.2008.02.022 · Cited by 29
Modulation of immune responses by the tumor suppressor p53
Lowe, J. M., Shatz, M., Resnick, M. A., & Menéndez, D. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.2 · Cited by 30
“Alterations of p53 function through mutation or misregulation in the p53 network are common features in human cancers with over 80-90% of tumors having an altered p53 pathway [1, 2].”
BackgroundZhou, W., Muggerud, A. A., Vu, P., Due, E. U., Sørlie, T., Børresen‐Dale, A., Wärnberg, F., & Langerød, A. (2009) · Molecular Oncology · doi:10.1016/j.molonc.2009.03.001 · Cited by 29
“All mutations have been previously reported and the fraction of hotspot versus rare mutations did not vary between the three groups (http:// www-p53.iarc.fr/; Petitjean et al., 2007).”
Backgroundp53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading
Guerra, E., Cimadamore, A., Simeone, P., Vacca, G., Lattanzio, R., Botti, G., Gatta, V., D’Aurora, M., Simionati, B., Piantelli, M., et al. (2016) · BMC Cancer · doi:10.1186/s12885-016-2713-3 · Cited by 29
“Insertions or deletions (indels) of the TP53 gene (Additional file 5: Table S5) were shown to carry the highest prognostic weight [29]; such mutations were identified and matched against those listed in the IARC database [29].”
BackgroundDeng, Q., Hu, H., Yu, X., Liu, S., Wang, L., Chen, W., Zhang, C., Zeng, Z., Cao, Y., Xu-Monette, Z. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13002-x · Cited by 32
Tetramerization‐defects of p53 result in aberrant ubiquitylation and transcriptional activity
Lang, V., Pallara, C., Zabala‐Letona, A., Lobato-Gil, S., Lopitz‐Otsoa, F., Farrás, R., Hjerpe, R., Torres-Ramos, M., Zabaleta, L., Blattner, C., et al. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.04.002 · Cited by 29
“After epidemiologic studies, 17% of germline mutations in patients with Li-Fraumeni syndrome occurred in the p53 OD (Petitjean et al., 2007).”
Background
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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