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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
Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., et al. (1990) · Science · doi:10.1126/science.1978757 · Cited by 3,765 · cited 1×
“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].”
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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Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.006 · Cited by 1,069 · 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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Shirole, N. H., Pal, D., Kastenhuber, E. R., Şentürk, Ş., Boroda, J. U., Pisterzi, P., Miller, M., Munoz, G., Anderluh, M., Ladanyi, M., et al. (2016) · eLife · doi:10.7554/elife.17929 · Cited by 80
“…studies spurred by the observation that TP53 missense mutations do not have a uniform distribution; rather, they occur more frequently at specific residues (R175, G245, R248, R249, R273 and R282) often referred to as ‘hotspot’ TP53 mutation sites (Petitjean et al., 2007; Brosh and Rotter, 2009).”
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“A vast majority yield single amino acid changes in the DNA binding domain of the protein (1).”
The Paradox of p53: What, How, and Why?Preprint
Aylon, Y., & Oren, M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026328 · Cited by 81
“The centrality of p53 for tumor suppression is dramatically illustrated by the fact that it is the most frequently mutated gene in human cancer (Petitjean et al. 2007).”
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Translational approaches targeting the p53 pathway for anti‐cancer therapy
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“The Y220C mutation, which is among the 10 most frequent p53 mutations (Petitjean et al., 2007), destabilizes the p53 protein and creates a crevice on the p53 surface that is opposite to the DBD (Joerger et al.”
BackgroundLi, J.-P., Zhang, X.-M., Zhang, Z., Zheng, L.-H., Jindal, S., & Liu, Y. (2019) · Medicine · doi:10.1097/md.0000000000015449 · Cited by 85
“In fact, 3 quarters of TP53 mutations are missense substitutions rather than truncation/deletion mutations.([30]) Previous studies reported that IHCdetected p53 reflected the mutant p53 and indicated poor prognosis in primary breast cancer.”
BackgroundNia, A. B., Kim, S.-I., Hainaut, P. L., & Pfeifer, G. P. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.06.002 · Cited by 78
Self-citationAssociation of the germline TP53R337H mutation with breast cancer in southern Brazil
Assumpção, J. G., Seidinger, A. L., Mastellaro, M. J., Ribeiro, R. C., Zambetti, G. P., Ganti, R., Srivastava, K., Shurtleff, S. A., Pei, D., Zeferino, L. C., et al. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-357 · Cited by 78
“It is also the most frequently reported germline mutation in the International Agency for Research on Cancer database [26,27], predominantly because of its association with most pediatric ACT cases (~80%–95%) in southern Brazil [4,5].”
BackgroundHuang, M., Tailor, J. K., Zhen, Q., Gillmor, A. H., Miller, M. L., Weishaupt, H., Chen, J., Zheng, T., Nash, E. K., McHenry, L. K., et al. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.05.013 · Cited by 75
“…is unlikely to act as a dominant negative, as (1) it is located outside of the DNA-binding domain, where most dominant-negative p53 mutations occur (Petitjean et al., 2007); (2) p53 was not detected by immunohistochemistry (IHC) in WTC10 MYCN tumors (Figures S1B and S1C); and (3) control WTC10 NES…”
TP53Mutations in Hypodiploid Acute Lymphoblastic LeukemiaPreprint
Comeaux, E. Q., & Mullighan, C. G. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026286 · Cited by 77
Genome interpretation using in silico predictors of variant impact
Katsonis, P., Wilhelm, K. O., Williams, A. M., & Lichtarge, O. (2022) · Human Genetics · doi:10.1007/s00439-022-02457-6 · Cited by 86
“…sources are available for somatic and germline variants, such as COS-MIC (Tate et al. 2019), International Agency for Research on Cancer (IARC) (Petitjean et al. 2007), Database of Curated Mutations (DoCM) (Ainscough et al. 2016), CanProVar (Li et al. 2010), and BRCA Exchange (Cline et al.…”
BackgroundJordan, J. J., Inga, A., Conway, K., Edmiston, S. N., Carey, L., Wu, L., & Resnick, M. A. (2010) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0442 · Cited by 77
“Interestingly, p53 is unique in comparison with other transcription factors in that >75% of mutations that occur in this tumor suppressor are single amino acid changes that result in missense mutations (7).”
BackgroundMethodInfluentialNerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator
Zhou, X. Y., Hao, Q., Liao, P., Luo, S., Zhang, M., Hu, G., Liu, H., Zhang, Y.-W., Cao, B., Baddoo, M., et al. (2016) · eLife · doi:10.7554/elife.15099 · Cited by 84
“Several of these cancers, such as breast cancer, melanoma, osteocarcoma, and neuroblastoma, often display less or no TP53 mutations (Petitjean et al., 2007; Soussi et al., 2005).”
BackgroundYe, J., Jiang, X., Dong, Z., Hu, S., & Xiao, M. (2019) · Cancer Management and Research · doi:10.2147/cmar.s217944 · Cited by 79
Conservation of DNA-binding specificity and oligomerisation properties within the p53 family
Brandt, T., Petrovich, M., Joerger, A. C., & Veprintsev, D. B. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-628 · Cited by 77
“p53 is at the centre of a tumour suppressor network [4,5], and, as such, is essential for the prevention of cancer [6,7].”
BackgroundInactivation and Inducible Oncogenic Mutation of p53 in Gene Targeted Pigs
Leuchs, S., Saalfrank, A., Merkl, C., Flisikowska, T., Edlinger, M., Durkovic, M., Rezaei, N., Kurome, M., Zakhartchenko, V., Kessler, B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043323 · Cited by 76
“A survey of somatic p53 mutations compiled by the International Agency for Research on Cancer reveals R175H as the most frequent missense mutation in many sporadic human cancers [9].”
BackgroundBlombery, P. A., Thompson, E. R., Ryland, G. L., Joyce, R., Byrne, D. J., Khoo, C., Lade, S., Hertzberg, M., Hapgood, G., Marlton, P. V., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26308 · Cited by 75
“The TP53 Arg249Lys mutation has not been described in LiFraumeni kindreds, however it has been observed multiple times as an acquired variant in diverse malignancies as well as being categorised as non-functional in the TP53 IARC database [22].”
BackgroundMurray, M. Y., Rushworth, S. A., Zaitseva, L., Bowles, K. M., & MacEwan, D. J. (2013) · Cell Cycle · doi:10.4161/cc.25251 · Cited by 75
Mutant TP53 Posttranslational Modifications: Challenges and Opportunities
Nguyen, T., Menéndez, D., Resnick, M. A., & Anderson, C. W. (2014) · Human Mutation · doi:10.1002/humu.22506 · Cited by 77
“Alteration of the TP53 gene itself or perturbations in TP53 signaling pathways are the most frequent events in tumorigenesis [Petitjean et al., 2007] and can be considered hallmarks of cancer cells [Pfeifer and Hainaut, 2011].”
BackgroundCancer-associated p53 Tetramerization Domain Mutants
Kamada, R., Nomura, T., Anderson, C. W., & Sakaguchi, K. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.174698 · Cited by 79
30 years and a long way into p53 research
Hainaut, P. L., & Wiman, K. G. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70198-6 · Cited by 80
Self-citationPaleček, E., Ostatná, V., Černocká, H., Joerger, A. C., & Fersht, A. R. (2011) · Journal of the American Chemical Society · doi:10.1021/ja201006s · Cited by 75
Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond
Teoh, S. T., & Lunt, S. Y. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1406 · Cited by 77
“The high rate of evolution within tumors is driven in large part by functional loss of genes involved in DNA damage repair, particularly p53.(19,20) Indeed, the original theory of cancer metastasis states that progression to the metastatic stage is due to clonal evolution and sequential acquisition of pro-metastatic t…”
BackgroundAn update on the central nervous system manifestations of Li–Fraumeni syndrome
Orr, B. A., Clay, M. R., Pinto, E. M., & Kesserwan, C. A. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02055-3 · Cited by 80
Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterationsPreprint
Tamborero, D., Rubio-Pérez, C., Deu-Pons, J., Schroeder, M. P., Vivancos, A. P., Rovira, A., Tusquets, I., Albanell, J., Rodon, J. A., Tabernero, J. M., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/140475 · Cited by 74
Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer
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p53 family members in cancer diagnosis and treatment
Machado-Silva, A., Perrier, S., & Bourdon, J. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.005 · Cited by 73
Eldar, A., Rozenberg, H., Diskin‐Posner, Y., Rohs, R., & Shakked, Z. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt630 · Cited by 77
“Mutations in the p53 gene that lead to inactivation of the protein are observed in 50% of human cancers (8,9).”
BackgroundLi, X., Wu, B. J., Chung, L. W. K., & Huang, W. (2015) · Oncotarget · doi:10.18632/oncotarget.5879 · Cited by 73
“1 and encodes the p53 protein, is one of the most frequent targets for mutation in human cancers [1, 2].”
Darb‐Esfahani, S., Denkert, C., Stenzinger, A., Salat, C., Sinn, B. V., Schem, C., Endris, V., Klare, P., Schmitt, W., Blohmer, J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11891 · Cited by 80
“Point mutations were uploaded into the IARC P53 Database (version R17, November 2013) [24] and the following parameters were assessed: effect on DNA structure, effect on protein structure and function (transactivation class, SIFT class), potential gain-offunction.”
MethodCell Fusion Connects Oncogenesis with Tumor Evolution
Zhou, X., Merchak, K., Lee, W., Grande, J. P., Cascalho, M., & Platt, J. L. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.03.014 · Cited by 72
“To address that possibility, as much as possible, we compared the region of rat Tp53 homologous to human exons 5 to 8 in which mutations are usually found in tumors.(56) The sequences from the nine colonies were identical with wild type, making it highly improbable that variants caused transformation in these cells.”
Biological Hallmarks of Cancer in Alzheimer’s Disease
Nudelman, K. N. H., McDonald, B. C., Lahiri, D. K., & Saykin, A. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1591-5 · Cited by 73
Biomarkers of laryngeal squamous cell carcinoma: a review
Cavaliere, M., Bisogno, A., Scarpa, A., D'Urso, A., Marra, P., Colacurcio, V., Luca, P. D., Ralli, M., Cassandro, E., & Cassandro, C. (2021) · Annals of Diagnostic Pathology · doi:10.1016/j.anndiagpath.2021.151787 · Cited by 72
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“Recently, several studies have identified that the mutant p53 executes transcription and nontranscription activities.(2,3) Several p53 mutants with a low level of transcriptional activation function were also shown to induce apoptosis in cancer cells demonstrating nontranscriptional apoptotic ability of mutant p53.”
BackgroundBrázdová, M., Quante, T., Tögel, L., Walter, K., Loscher, C., Tichý, V., Činčárová, L., Deppert, W., & Tolstonog, G. V. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn1085 · Cited by 72
“These domains are rarely mutated in human tumor cells (2,3) and are crucial for interactions with proteins of transcription complexes (15,16).”
BackgroundThe p53 mutation “gradient effect” and its clinical implications
Zambetti, G. P. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21217 · Cited by 71
“…the efforts of Hainaut and associates at the International Agency for Research on Cancer in Lyon, France, who have compiled an extensive database summarizing the somatic mutations of p53 that have been observed in more than 23,000 tumor samples (wwwp53.iarc.fr/index.html) (Petitjean et al., 2007).”
BackgroundThe potential role of miRNAs and exosomes in chemotherapy in ovarian cancer
Alharbi, M. G., Zuñiga, F. A., Elfeky, O. W. M., Guanzon, D., Lai, A., Rice, G. E., Perrin, L. C., Hooper, J. D., & Salomón, C. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0019 · Cited by 73
Carney complex with adrenal cortical carcinoma
Morin, E., Mete, O., Wasserman, J. D., Joshua, A. M., Asa, S. L., & Ezzat, S. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2321 · Cited by 69
“9% of tumors in patients with germline p53 mutations [associated with the Li-Fraumeni syndrome (22, 23)] but less than 1% of all cancers in all individuals (24) (International Agency for Research on Cancer, TP53 database, http://wwwp53.”
BackgroundFrancisco, G., Menezes, P. R., Eluf‐Neto, J., & Chammas, R. J. (2010) · International Journal of Cancer · doi:10.1002/ijc.25710 · Cited by 72
“fr), where the percentage of TP53 mutations show considerable variance between cancer types.(43,44) However, tissue-specificity alone does not account for the observed variation in effects because large interstudy heterogeneity within a tissue-specific group was also observed.”
BackgroundSilva, J. L., Rangel, L. P., da Costa, D. C. F., Cordeiro, Y., & Gallo, C. V. D. M. (2013) · Bioscience Reports · doi:10.1042/bsr20130065 · Cited by 72
Multilocus Inherited Neoplasia Alleles Syndrome
Whitworth, J., Skytte, A., Sunde, L., Lim, D., Arends, M. J., Happerfield, L. C., Frayling, I. M., van Minkelen, R., Woodward, E. R., Tischkowitz, M. D., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2015.4771 · Cited by 70
Scagliotti, G., Kang, J. H., Smith, D. C., Rosenberg, R. K., Park, K., Kim, S.-W., Su, W., Boyd, T. E., Richards, D., Novello, S., et al. (2016) · Investigational New Drugs · doi:10.1007/s10637-016-0368-1 · Cited by 70
“A possible explanation for this difference may be due to a higher sensitivity when combining both methods [26].”
BackgroundThe T-ALL related gene BCL11B regulates the initial stages of human T-cell differentiation
Ha, V. L., Luong, A., Li, F., Casero, D., Malvar, J., Kim, Y. M., Bhatia, R., Crooks, G. M., & Parekh, C. (2017) · Leukemia · doi:10.1038/leu.2017.70 · Cited by 70
Genetic Modifiers of the p53 PathwayPreprint
Basu, S., & Murphy, M. E. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026302 · Cited by 72
“First, there are a larger than normal number of SNPs in TP53, with 85 polymorphisms identified within 19 kilobases of DNA (Petitjean et al. 2007).”
BackgroundKucab, J. E., Phillips, D. H., & Arlt, V. M. (2010) · FEBS Journal · doi:10.1111/j.1742-464x.2010.07676.x · Cited by 70
Viotti, J., Duplan, E., Caillava, C., Condat, J., Goiran, T., Giordano, C., Marie, Y., Idbaïh, A., Delattre, J.-Y., Honnorat, J., et al. (2013) · Oncogene · doi:10.1038/onc.2013.124 · Cited by 70
Hollstein, M. C., Moriya, M., Grollman, A. P., & Olivier, M. (2013) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2013.02.003 · Cited by 69
“fr/) includes data on the prevalence and patterns of TP53 mutations in human cancers, annotations of tumor phenotype, patient characteristics, and the structural and functional impact of the mutations [10].”
BackgroundSelf-citationKurokawa, M., Kim, J., Geradts, J., Matsuura, K., Liu, L., Xu, R., Xia, W., Ribar, T. J., Henao, R., Dewhirst, M. W., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2003741 · Cited by 68
Perdomo, S. P., Avogbe, P. H., Foll, M., Abedi‐Ardekani, B., Facciolla, V. L., Anantharaman, D., Chopard, P., Calvez‐Kelm, F. L., Vilensky, M., Polesel, J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20004 · Cited by 71
“More than 80% of overall mutations corresponded to missense variants, all localized in the DNA binding domain (aminoacids 102-292) and 86% were non-functional variants according to the functional classification based on the overall transcription activity [17] (Figure 3B and Supplementary Table 2).”
BackgroundNot all p53 gain-of-function mutants are created equal
Mello, S. S., & Attardi, L. D. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.53 · Cited by 69
Caponio, V. C. A., Troiano, G., Adipietro, I., Zhurakivska, K., Arena, C., Mangieri, D., Mascitti, M., Cirillo, N., & Muzio, L. L. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0984-6 · Cited by 68
“Inherited TP53 mutations lead to a wide spectrum of early-onset cancers.(14) In contrast to other tumour-suppressor genes that are mainly altered by truncating mutations, the majority of TP53 mutations are missense substitutions (75%).”
BackgroundPredicting Positive p53 Cancer Rescue Regions Using Most Informative Positive (MIP) Active Learning
Danziger, S. A., Baronio, R., Ho, L. S., Hall, L., Salmon, K. A., Hatfield, G. W., Kaiser, P., & Lathrop, R. H. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000498 · Cited by 68
“We considered ten p53 cancer mutants that are commonly found in human cancer [12] and can be constructed so that they differ by two or more nucleic acid changes from the wild-type.”
BackgroundInfluentialMishra, R., Nagini, S., & Rana, A. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0300-x · Cited by 70
“Although mutational inactivation of p53 has been reported in nearly half of the oral cancer population, in the subpopulation of OSCC cases without p53 mutations the mechanism of p53 inactivation is still far from clear [17].”
BackgroundTargeting p53 as a therapeutic strategy in sensitizing TRAIL-induced apoptosis in cancer cells
Zhao, J., Lü, Y., & Shen, H. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.09.040 · Cited by 72
Coffill, C. R., Muller, P. A. J., Oh, H. K., Neo, S. P., Hogue, K. A., Cheok, C. F., Vousden, K. H., Lane, D. P., Blackstock, W. P., & Gunaratne, J. (2012) · EMBO Reports · doi:10.1038/embor.2012.74 · Cited by 68
“Of the missense mutations reported in the IARC TP53 database, the largest number of single base changes ( 4 7.5% each) occur at amino acid positions 248 and 273 ((Database R15), [2]).”
InfluentialBoth Germ Line and Somatic Genetics of the p53 Pathway Affect Ovarian Cancer Incidence and Survival
Bartel, F., Jung, J., Böhnke, A., Gradhand, E., Zeng, K., Thomssen, C., & Hauptmann, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1192 · Cited by 67
A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations
Takai, A., Toyoshima, T., Uemura, M., Kitawaki, Y., Marusawa, H., Hiai, H., Yamada, S., Okazaki, I., Honjo, T., Chiba, T., et al. (2008) · Oncogene · doi:10.1038/onc.2008.415 · Cited by 67
“fr/) (Petitjean et al., 2007).”
Punganuru, S. R., Madala, H. R., Venugopal, S. N., Samala, R., Mikelis, C. M., & Srivenugopal, K. S. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.10.052 · Cited by 67
Kim, J., Park, K., Jung, H. H., Lee, E., Cho, E. Y., Lee, K. H., Bae, S. Y., Lee, S. K., Kim, S. W., Lee, J. E., et al. (2016) · Cancer Research and Treatment · doi:10.4143/crt.2015.430 · Cited by 69
Malonia, S. K., Dutta, P., Santra, M. K., & Green, M. R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510929112 · Cited by 66
“The importance of this anticancer mechanism is highlighted by the mutation or functional inactivation of the p53 gene in more than 50% of human cancers (2, 3).”
BackgroundDifferent mutation profiles associated to P53 accumulation in colorectal cancer
López, I., Oliveira, L. P., Tucci, P., Álvarez-Valín, F., Coudry, R. A., & Marín, M. (2012) · Gene · doi:10.1016/j.gene.2012.02.011 · Cited by 71
High Frequency of Germline TP53 Mutations in a Prospective Adult-Onset Sarcoma Cohort
Mitchell, G., Ballinger, M. L., Wong, S. Q., Hewitt, C., James, P. A., Young, M., Cipponi, A., Pang, T. W.-Y., Goode, D. L., Dobrovic, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069026 · Cited by 66
“reported somatically [19], but 10 are reported here for the first time in the germline.”
BackgroundAbscopal effect of radiation therapy: Interplay between radiation dose and p53 status
Strigari, L., Mancuso, M., Ubertini, V., Soriani, A., Giardullo, P., Benassi, M., D’Alessio, D., Leonardi, S., Soddu, S., & Bossi, G. (2013) · International Journal of Radiation Biology · doi:10.3109/09553002.2014.874608 · Cited by 66
“Th is gene is the most common target for genetic alteration in human tumours: More than 50% of all human cancers carry mutations within the p53 locus (Hainaut and Hollstein 2000, Petitjean et al. 2007).”
BackgroundMüller‐Thomas, C., Rudelius, M., Rondak, I., Haferlach, T., Schanz, J., Huberle, C., Schmidt, B., Blaser, R., Kremer, M., Peschel, C., et al. (2014) · Haematologica · doi:10.3324/haematol.2014.104760 · Cited by 67
“5-Aza cycles Median (range) 4 (1-29) 5 (1-22) 0.”
Tornesello, M. L., Annunziata, C., Buonaguro, L., Losito, S., Greggi, S., & Buonaguro, L. (2014) · Journal of Translational Medicine · doi:10.1186/s12967-014-0255-5 · Cited by 66
Lee, D. S., Yoon, S., Looi, L., Kang, P. C. E., Kang, I. N., Sivanandan, K., Ariffin, H., Thong, M., Chin, K. F., Taib, N. A. M., et al. (2012) · Breast Cancer Research · doi:10.1186/bcr3172 · Cited by 67
“(1)Reported in IARC TP53 database [18].”
BackgroundInfluentialDomain landscapes of somatic mutations in cancer
Nehrt, N. L., Peterson, T. A., Park, D., & Kann, M. G. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-s4-s9 · Cited by 65
“Is the whole protein responsible for the disruption that promotes tumor growth, or are only some of the functional units of the proteins relevant? For instance, the P53 domain, also known as the P53 DNA-binding domain, contains over 90% of the known TP53 mutations [24], even though the P53 DNA-binding domain covers ap…”
BackgroundWeng, M.-W., Lee, H., Choi, B., Wang, H., Hu, Y., Mehta, M., Desai, D. H., Amin, S., Zheng, Y., & Tang, M.-S. (2017) · Oncotarget · doi:10.18632/oncotarget.15313 · Cited by 65
“…photodimer formation; p53 mutational hotspots in cigarette smoke (CS)-related lung cancer are located at cytosine methylated -CG- sites that are preferential binding locations for CS carcinogens such as the diol epoxide forms of polycyclic aromatic hydrocarbons (PAHs) and acrolein (Acr) [5, 10-13].”
Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis
Lopes, C. A. M., Mesquita, M., Cunha, A. I., Cardoso, J., Carapeta, S., Laranjeira, C., Pinto, A. E., Pereira‐Leal, J. B., Pereira, A. D., Bettencourt‐Dias, M., et al. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201711191 · Cited by 65
“R175H and R248W are known hotspot mutations in BE neoplasia and other tumors (Fig. 2; Petitjean et al., 2007; Weaver et al., 2014).”
BackgroundInfluentialWalsh, M. F., Ritter, D., Kesserwan, C. A., Sonkin, D., Chakravarty, D., Chao, E., Ghosh, R., Kemel, Y. M., Wu, G., Lee, K., et al. (2018) · Human Mutation · doi:10.1002/humu.23640 · Cited by 63
“The p53 transactivation assay is an established functional assay for TP53 variants (Kato et al., 2003; Monti et al., 2007; Petitjean et al., 2007).”
MethodCell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells
Surget, S., Chiron, D., Gomez‐Bougie, P., Descamps, G., Ménoret, E., Bataille, R., Moreau, P., Gouill, S. L., Amiot, M., & Pellat‐Deceunynck, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0487 · Cited by 64
“TP53 is frequently mutated and/or deleted in tumor cells (5).”
BackgroundMechanical insights into the regulation of programmed cell death by p53 via mitochondria
Yamada, K., & Yoshida, K. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.02.009 · Cited by 64
Kamaraj, B., & Bogaerts, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134638 · Cited by 62
Holstege, H. H., Horlings, H. M., Velds, A., Langerød, A., Børresen‐Dale, A., van de Vijver, M. J., Nederlof, P. M., & Jonkers, J. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-654 · Cited by 63
“All missense mutations found in the BRCA1-mutated and luminal-J tumor groups were classified according to their predicted effect on p53 function as determined by the Sorting Intolerant from Tolerant algorithm SIFT; [27,28], as used in the IARC TP53 database [29,30].”
Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC
Friboulet, L., Barrios-Gonzales, D., Commo, F., Olaussen, K. A., Vagner, S., Adam, J., Goubar, A., Dorvault, N., Lazar, V., Job, B., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0790 · Cited by 64
“The details of mutations detected are presented in Supplementary Table S2 (26).”
BackgroundCOLD-PCR Enrichment of Rare Cancer Mutations prior to Targeted Amplicon Resequencing
Milbury, C. A., Correll, M., Quackenbush, J. F., Rubio, R., & Makrigiorgos, G. M. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2011.176198 · Cited by 64
Molecular epidemiology of adrenocortical tumors in southern Brazil
Custódio, G., Komechen, H., Figueiredo, F. R. O., Fachin, N. D., Pianovski, M. A. D., & Figueiredo, B. C. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.10.019 · Cited by 63
“) are associated with a large spectrum of genetic alterations: mutations inactivating p53 (of which >80% are in the DNA-binding domain (DBD); 50% of all human tumors have such a mutation) (Petitjean et al., 2007; Vousden and Lu, 2002).”
Structural and Drug Targeting Insights on Mutant p53
Gomes, A. S., Ramos, H., Inga, A., Sousa, E., & Saraiva, L. (2021) · Cancers · doi:10.3390/cancers13133344 · Cited by 63
“Missense mutations are the most frequent alterations in TP53 (over 75%) and mainly occur in the DBD region (over 80%) [59].”
BackgroundOhashi, T., Idogawa, M., Sasaki, Y., Suzuki, H., & Tokino, T. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0330-t · Cited by 63
“However, the rate of p53 mutation in colorectal cancers is approximately 40% (2), whereas the expression of AKR1B10 is decreased in most colorectal cancers (Fig.”
BackgroundDrastic Effect of GermlineTP53Missense Mutations in Li-Fraumeni Patients
Zerdoumi, Y., Aury‐Landas, J., Bonaïti‐Pellié, C., Derambure, C., Sesboüé, R., Renaux‐Petel, M., Frébourg, T., Bougeard, G., & Flaman, J. (2012) · Human Mutation · doi:10.1002/humu.22254 · Cited by 63
“, 2000], on the frequent detection of somatic genomic deletions of TP53 in human cancers, and on the identification of null somatic and germline TP53 mutations [Petitjean et al., 2007].”
BackgroundInfluentialCzapiewski, P., Kunc, M., & Haybaeck, J. (2016) · Oncotarget · doi:10.18632/oncotarget.9683 · Cited by 63
“Somatic TP53 mutations occur in about 40,6% of head and neck cancers [36].”
BackgroundPang, J., Savas, P. S., FELLOWES, A. P., Arnau, G. M., Kader, T., Vedururu, R., Hewitt, C., Takano, E. A., Byrne, D. J., Choong, D. Y., et al. (2017) · Modern Pathology · doi:10.1038/modpathol.2017.21 · Cited by 63
TP53 in Biology and Treatment of Osteosarcoma
Synoradzki, K. J., Bartnik, E., Czarnecka, A. M., Fiedorowicz, M., Firlej, W., Brodziak, A., Stasinska, A., Rutkowski, P. L., & Grieb, P. (2021) · Cancers · doi:10.3390/cancers13174284 · Cited by 66
“The most frequent amino acid substitutions in these codons are classified as non-functional [78,79].”
BackgroundPurkait, S., Jha, P., Sharma, M. C., Suri, V. S., Sharma, M. K., Kale, S. S., & Sarkar, C. (2013) · Neuropathology · doi:10.1111/neup.12014 · Cited by 62
“TP53 coding regions from exons 2 to 11 were analyzed using the direct sequencing protocol as described in the International Agency for Research on Cancer (IARC) p53 database.(25,27)”
MethodLadelfa, M. F., Toledo, M. F., Laiseca, J. E., & Monte, M. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3652 · Cited by 60
“The relevance of p53 as tumor suppressor has been demonstrated by its inactivating high mutation rate found in tumors (115) and by the number of oncogenic viral proteins (87) or tumorspecific proteins (105, 160) that target p53 function.”
BackgroundNadal, E., Chen, G., Gallegos, M., Lin, L., Ferrer-Torres, D., Truini, A., Wang, Z., Lin, J., Reddy, R. M., Llatjós, R., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0736 · Cited by 62
Meng, X., Sun, W., Yu, J., Zhou, Y., Gu, Y., Han, J., Zhou, L., Jiang, X., & Wang, C. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.10.018 · Cited by 63
“Approximately half of all CRCs show TP53 gene mutations, which are associated with poor clinical outcome.(17) p53 functions primarily as a transcription factor to regulate the expression of various target genes that participate in cell cycle arrest, programmed cell death, DNA repair, proliferation, apoptosis, angiogen…”
BackgroundSu, X., Feng, C., Wang, S., Shi, L., Gu, Q., Zhang, H., Lan, X., Zhao, Y., Qiang, W., Ji, M., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00762-7 · Cited by 66
“Loss of p53 function, mainly by mutations in p53, has been revealed to be a common feature in the majority of human cancers, including breast cancer [10, 11].”
BackgroundTargeting mutant p53: a key player in breast cancer pathogenesis and beyond
Qayoom, H., Haq, B. U., Sofi, S., Jan, N., Jan, A., & Mir, M. A. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01863-9 · Cited by 68
“As to the most recent version of the International Agency for Research on Cancer (IARC) TP53 database (http:// www-p53. iarc. fr/), which is a part of COSMIC, missense mutations account for over 70% of TP53 changes linked to breast cancer [51].”
BackgroundPoint-Mutation Effects on Charge-Transport Properties of the Tumor-Suppressor Gene p53
Shih, C. T., Roche, S., & Römer, R. A. (2008) · Physical Review Letters · doi:10.1103/physrevlett.100.018105 · Cited by 61
Identification of Preferred Chemotherapeutics for Combining with a CHK1 Inhibitor
Xiao, Y., Ramiscal, J. A. B., Kowanetz, K., Nagro, C. J. D., Malek, S., Evangelista, M., Blackwood, E. R., Jackson, P. K., & O’Brien, T. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0404 · Cited by 60
“11 | P a g e Synergy between Gemcitabine and GNE-783 is greater in p53 deficient cells As our initial screen used HT-29 cells which are p53 mutant (R273H) (27), we expanded this screen to other cell lines to evaluate the importance of p53 status to chemopotentiation.”
BackgroundLee, H., Wang, H., Weng, M.-W., Chiu, C., Huang, W. C. W., Lepor, H., Wu, X., Rom, W. N., Chen, L., & Tang, M.-S. (2015) · Oncotarget · doi:10.18632/oncotarget.5429 · Cited by 61
Myelodysplastic Syndromes Arising in Patients With Germline TP53 Mutation and Li-Fraumeni Syndrome
Talwalkar, S. S., Yin, C. C., Naeem, R. C., Hicks, J. M., Strong, L. C., & Abruzzo, L. V. (2010) · Archives of Pathology & Laboratory Medicine · doi:10.5858/2009-0015-oa.1 · Cited by 60
Relationships between p53 mutation, HPV status and outcome in oropharyngeal squamous cell carcinoma
Hong, A., Zhang, X., Jones, D., Veillard, A.-S., Zhang, M., Martin, A. J., Lyons, J. G., Lee, C. S., & Rose, B. R. (2016) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2016.02.009 · Cited by 60
Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis
Guo, S. (2018) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12221 · Cited by 58
Illuminating p53 function in cancer with genetically engineered mouse models
Garcia, P. B., & Attardi, L. D. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.12.014 · Cited by 65
Clinical utility of anti-p53auto-antibody: Systematic review and focus on colorectal cancer
Suppiah, A. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i29.4651 · Cited by 62
Jones, R. J., Bjorklund, C. C., Baladandayuthapani, V., Kuhn, D. J., & Orlowski, R. Z. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0135 · Cited by 61
“Of particular interest was the fact that MI-63- and Nutlin-resistant H929 cells both carried the R248Q and R175H hot spot mutations, which are the most common p53 mutation in B-cell malignancies (43).”
BackgroundFu, Y., Edvardsen, H., Kaushiva, A., Arhancet, J. P., Howe, T. M., Kohaar, I., Porter-Gill, P. A., Shah, A., Landmark‐Høyvik, H., Fosså, S. D., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-113 · Cited by 61
“Somatic mutations in the TP53 gene are found in 20 - 30% of all breast tumors [28,29], but the frequency varies by tumor stage and subtype.”
BackgroundOncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism
Kim, H., Yoo, S., Zhou, R., Xu, A., Bernitz, J. M., Yuan, Y., Gomes, A., Daniel, M. G., Su, J., Demicco, E. G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814044115 · Cited by 59
“Therefore, it is no surprise that aberrant P53 expression contributes significantly to cancer development (Brosh & Rotter, 2009; Goh et al, 2011; Muller & Vousden, 2014; 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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