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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].”
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
Denissenko, M. F., Pao, A., Tang, M.-S., & Pfeifer, G. P. (1996) · Science · doi:10.1126/science.274.5286.430 · Cited by 1,650 · cited 1×
“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
Olivier, M., Eeles, R., Hollstein, M., Khan, M. A., Harris, C. C., & Hainaut, P. (2002) · Human Mutation · doi:10.1002/humu.10081 · Cited by 1,248 · cited 1×
“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].”
BackgroundGain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
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].”
Backgroundp53 and Human Cancer: The First Ten Thousand Mutations
Hainaut, P. L., & Hollstein, M. C. (1999) · Advances in cancer research · doi:10.1016/s0065-230x(08)60785-x · Cited by 999 · cited 1×
“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.”
BackgroundSelf-citationKato, S., Han, S., Liu, W., Otsuka, K., Shibata, H., Kanamaru, R., & Ishioka, C. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1431692100 · Cited by 895 · cited 2×
“…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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Dai, G., Wang, L., Wen, Y., Ren, X., & Zuo, S. (2019) · Oncology Letters · doi:10.3892/ol.2019.11068 · Cited by 47
“Furthermore, AKR1B10 is one of the direct transcriptional targets of the p53 gene (34,57).”
Backgroundp53 mutation is common in microsatellite stable, BRAF mutant colorectal cancers
Bond, C., Umapathy, A., Ramsnes, I., Greco, S. A., Zhao, Z., Mallitt, K., Buttenshaw, R. L., Montgomery, G. W., Leggett, B., & Whitehall, V. (2011) · International Journal of Cancer · doi:10.1002/ijc.26175 · Cited by 47
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Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis
Ehrhardt, H., Wachter, F., Grunert, M., & Jeremias, I. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.179 · Cited by 46
“To prove the general significance of the observed phenotype across different tumor entities, the hematopoietic T cell leukemia cell line CEM was additionally studied, which expresses mutant but functionally active p53.(11,18,23,24,28) siRNA against cyclinB and E arrested the cell cycle in G2 and G1, respectively, also…”
MethodResultA balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer
Miller, J. J., Gaiddon, C., & Storr, T. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00163e · Cited by 47
Clinical impact of TP53 alterations in adrenocortical carcinomas
Waldmann, J., Patsalis, N., Fendrich, V., Langer, P., Saeger, W., Chaloupka, B., Ramaswamy, A., Faßnacht, M., Bartsch, D. K., & Slater, E. P. (2011) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-011-0868-6 · Cited by 45
“Furthermore not all coding exons of the TP53 gene were analyzed due to the compelling 97% of ACC-associated TP53 mutations in the herein assessed exons (5, 6, 7, 8, and 10) according to the IARCC database [23].”
MethodResultInfluentialNoureddine, M., Menéndez, D., Campbell, M. R., Bandele, O. J., Horvath, M. M., Wang, X., Pittman, G. S., Chorley, B. N., Resnick, M. A., & Bell, D. A. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000462 · Cited by 45
“binding could provide insight into tumor biology, carcinogenesis and treatment response [35,36].”
BackgroundMethodLionetti, M., Barbieri, M., Manzoni, M., Fabris, S., Bandini, C., Todoerti, K., Nozza, F., Rossi, D., Musto, P., Baldini, L., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7241 · Cited by 45
“Furthermore, virtually all the missense mutations identifi ed in our study are classifi ed as non-functional [ 23 ] in the IARC database (see Materials and Methods).”
BackgroundSievers, C. K., Zou, L. S., Pickhardt, P. J., Matkowskyj, K. A., Albrecht, D. M., Clipson, L. J., Bacher, J. W., Pooler, B. D., Moawad, F. J., Cash, B. D., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-312232 · Cited by 47
“This included the KRAS variant for polyp PF24 and the removal of the CTNNB1 variant in PF11.”
BackgroundIntratumour heterogeneity of p53 expression; causes and consequences
Xue, Y., Luis, B. S., & Lane, D. P. (2019) · The Journal of Pathology · doi:10.1002/path.5328 · Cited by 44
Warren, R. S., Atreya, C. E., Niedzwiecki, D., WEINBERG, V. K., Donner, D. B., Mayer, R. J., Goldberg, R. M., Compton, C. C., Zuraek, M. B., Ye, C., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0351 · Cited by 45
“Most mutations of TP53 are missensemutations that produce proteins with single amino acid changes and diminished tumor suppressor activity (2).”
Cameselle‐García, S., Abdulkader-Sande, S., Sánchez‐Ares, M., Rodríguez-Carnero, G., García-Gómez, J., Gudé, F., Abdulkader, I., & Cameselle‐Teijeiro, J. (2021) · Oncology Letters · doi:10.3892/ol.2021.12814 · Cited by 43
“genes, respectively (64‐66), and/or related to loss of function mutations in the TP53 gene (67), and other alterations (68,69).”
BackgroundTP53 Mutants in the Tower of Babel of Cancer Progression
Bisio, A., Ciribilli, Y., Fronza, G., Inga, A., & Monti, P. (2014) · Human Mutation · doi:10.1002/humu.22514 · Cited by 44
“The spectrum of TP53 germline mutations comprises many different alleles but the vast majority yields single amino-acid changes in the DBD of the protein [Petitjean et al., 2007].”
BackgroundProestling, K., Hebar, A., Pruckner, N., Márton, E., Vinatzer, U., & Schreiber, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047325 · Cited by 44
The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype
Ruijs, M., Broeks, A., Menko, F. H., Ausems, M. G. E. M., Wagner, A., Oldenburg, R. A., Meijers-Heijboer, H. E. J., Veer, L. J. V., & Verhoef, S. (2009) · Hereditary Cancer in Clinical Practice · doi:10.1186/1897-4287-7-4 · Cited by 45
“So far, 419 TP53-positive families have been reported (IARC mutation database, R13, November 2008 [7]).”
BackgroundGenetic causes of cancer predisposition in children and adolescents.
Saletta, F., Pozza, L. D., & Byrne, J. A. (2015) · PubMed · doi:10.3978/j.issn.2224-4336.2015.04.08 · Cited by 48
“Most TP53 mutations are missense alterations clustered at codons 175, 248 and 273 in the central DNA-binding domain (35), and are considered to be highly penetrant.”
BackgroundWright, D. G., Marchal, C., Hoang, K., Ankney, J. A., Nguyen, S. T., Rushing, A. W., Polakowski, N. J., Miotto, B., & Lemasson, I. (2015) · Oncotarget · doi:10.18632/oncotarget.6424 · Cited by 49
“While the status of p53 appears to vary among different sources of this line [48, 49], the cells we tested express the p53 protein [50, 51] and display activation of p21/CDKN1A and GADD45A expression following etoposide treatment.”
BackgroundDogs are man's best friend: in sickness and in health
Bentley, R. T., Ahmed, A. U., Yanke, A. B., Cohen‐Gadol, A., & Dey, M. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now109 · Cited by 44
Protective Effects of Garlic and Cinnamon Oils on Hepatocellular Carcinoma in Albino Rats
Aly, S. M., Fetaih, H., Hassanin, A. A. I., Abomughaid, M. M., & Ismail, A. A. (2019) · Analytical Cellular Pathology · doi:10.1155/2019/9895485 · Cited by 44
“(introns) which involved in transcriptional regulatory mechanisms [35, 36].”
BackgroundMahaira, L. G., Tsimplouli, C., Sakellaridis, N., Alevizopoulos, K., Demetzos, C., Han, Z., Pantazis, P., & DIMAS, K. S. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.04.065 · Cited by 46
Gomes, J., Magalhães, A., Michel, V., Amado, I. F., Aranha, P. C. D. R., Ovesen, R. G., Hansen, H. C. B., Gärtner, F., Reis, C. A., & Touati, E. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr329 · Cited by 47
“Mutation in the P53 tumor suppressor gene is the most common alteration found in human tumors (Petitjean et al., 2007).”
BackgroundRoth, J. J., Santi, M., Rorke-Adams, L. B., Harding, B. N., Busse, T., Tooke, L. S., & Biegel, J. A. (2014) · Cancer Genetics · doi:10.1016/j.cancergen.2014.03.002 · Cited by 43
“This alteration was identified in one third of the LGGs (19 of 56 with the 7q34 duplication; 1 of 56 with 7q34 deletions), including approximately two thirds of the classic PAs (16 of 26) as well as in 4 additional LGGs including: 3 PA-diffuse variants (11-162, 11448, and 12-042) and 1 pilomyxoid/PA (11-271) as demons…”
InfluentialKucab, J. E., STEEG, H. V., Luijten, M., Schmeiser, H. H., White, P. A., Phillips, D. H., & Arlt, V. M. (2015) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2015.01.013 · Cited by 45
“resource for studying the patterns and frequencies of these mutations in cancer [7].”
BackgroundCross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers
Holstege, H. H., van Beers, E., Velds, A., Liu, X., Joosse, S. A., Klarenbeek, S., Schut, E., Kerkhoven, R. M., Klijn, C. N., Wessels, L. F. A., et al. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-455 · Cited by 43
“Human TP53 mutations are somatic and can be acquired in myriad different ways, possibly resulting in different phenotypes [43].”
BackgroundWojnarowicz, P. M., Oros, K. K., Quinn, M. C. J., Arcand, S. L., Gambaro, K., Madore, J., Birch, A. H., de Ladurantaye, M., Rahimi, K., Provencher, D. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045484 · Cited by 44
“Most of the variants identified (Table S1) are suspected to affect p53 function and have been reported in various cancer samples by the IARC TP53 Database [32].”
ResultHai, J., Sakashita, S., Allo, G., Ludkovski, O., Ng, C., Shepherd, F. A., & Tsao, M. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000584 · Cited by 44
“673-2A>G, and deletion in the TP53 gene, respectively.(25) RG7388 potently inhibited cell growth in all three p53 wild-type lines (HLC 12, A549 and H1395), giving rise to the half maximal inhibitory concentration (IC 50 ) values ranging from 0.”
BackgroundFisher, O. M., Lord, S. J., Falkenback, D., Clemons, N. J., Eslick, G. D., & Lord, R. V. (2016) · Gut · doi:10.1136/gutjnl-2015-310888 · Cited by 43
Kim, D. W., Haydu, L. E., Joon, A. Y., Bassett, R. L., Siroy, A. E., Tetzlaff, M. T., Routbort, M. J., Amaria, R. N., Wargo, J. A., McQuade, J. L., et al. (2016) · Cancer · doi:10.1002/cncr.30463 · Cited by 43
TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
Grote, I., Bartels, S., Kandt, L. D., Bollmann, L., Christgen, H., Gronewold, M., Raap, M., Lehmann, U., Gluz, O., Nitz, U. A., et al. (2021) · Cancer Medicine · doi:10.1002/cam4.4376 · Cited by 43
Surveillance recommendations for patients with germline TP53 mutations
Ballinger, M. L., Mitchell, G., & Thomas, D. M. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000200 · Cited by 43
“Other characteristic LFS cancers are brain tumors and leukemias [7].”
BackgroundGreenblatt, M. S., Brody, L. C., Foulkes, W. D., Genuardi, M., Hofstra, R. M. W., Olivier, M., Plon, S. E., Sijmons, R. H., Sinilnikova, O. M., Spurdle, A. B., et al. (2008) · Human Mutation · doi:10.1002/humu.20889 · Cited by 43
“Other LSDBs, such as the IARC TP53 Mutation Database (wwwp53.iarc.fr) [Petitjean et al, 2007], the UMD TP53 Mutation Database (http://p53.free.fr/) [Soussi 2006], and the CDKN2A Mutation Database (https://biodesktop.uvm.edu/perl/p16) [Murphy et al, 2004] are maintained by single research groups and…”
MethodSelf-citationKey Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy
Chasov, V. V., Mirgayazova, R., Zmievskaya, E., Khadiullina, R., Valiullina, A., Clarke, J. R. S., Rizvanov, A. A., Baud, M. G. J., & Bulatov, E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01460 · Cited by 42
“The Y220C mutation is the ninth most frequent p53 missense mutant overall and is associated with over 100,000 new cancer cases per year worldwide, predominantly breast and ovarian cancer (18, 34).”
BackgroundPrevalence and impact of founder mutations in hereditary breast cancer in Latin America
Ashton‐Prolla, P., & Vargas, F. R. (2014) · Genetics and Molecular Biology · doi:10.1590/s1415-47572014000200009 · Cited by 42
Signaling pathways in follicular cell-derived thyroid carcinomas
Romitti, M., Ceolin, L., Siqueira, D. R., Ferreira, C. V., Wajner, S. M., & Maia, A. L. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1681 · Cited by 43
Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma
Ohnstad, H. O., Castro, R., Sun, J., Heintz, K., Vassilev, L. T., Bjerkehagen, B., Kresse, S. H., Meza‐Zepeda, L. A., & Myklebost, O. (2012) · Cancer · doi:10.1002/cncr.27837 · Cited by 42
“Median age at diagnosis (range), y 58 (8-87)”
BackgroundJha, P., Suri, V. S., Sharma, V., Singh, G., Sharma, M. C., Pathak, P., Chosdol, K., Jha, P., Suri, A., Mahapatra, A. K., et al. (2011) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2011.04.017 · Cited by 42
Origins of Injection-Site Sarcomas in Cats: The Possible Role of Chronic Inflammation—A Review
Woodward, K. (2011) · ISRN Veterinary Science · doi:10.5402/2011/210982 · Cited by 42
“The immediate reaction to a foreign body is acute inflammation, a protective mechanism which aims to remove the foreign body for example, by the killing and lysis of bacterial cells.”
BackgroundAssessment of TP53 Mutations in Benign and Malignant Salivary Gland Neoplasms
Gomes, C. C., Diniz, M. G., Orsine, L. A., Duarte, A. P., Fonseca–Silva, T., Conn, B., Marco, L. A. D., Pereira, C. M., & Gomez, R. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041261 · Cited by 43
“fr) [23], with the exception of the primers used to sequence exons 2 and 3 (Table S1).”
MethodGonçalves, A. P., Máximo, V., Lima, J. P., Singh, K. K., Soares, P., & Videira, A. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.006 · Cited by 46
“In addition, the fact that 143B cells harbor a point mutation at the DNA-binding domain of TP53 that translates to the substitution Arg156Pro [29], leading to a non-functional protein [28], further corroborates that a functional p53 is not required for the rotenone-induced cell cycle arrest.”
Quandt, J., Schlude, C., Bartoschek, M., Will, R. D., Cid-Arregui, Á., Schölch, S., Reißfelder, C., Weitz, J., Schneider, M. A., Wiemann, S., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1500671 · Cited by 42
Clinical aspects of TP53 gene inactivation in diffuse large B-cell lymphoma
Voropaeva, E. N., Pospelova, T. I., Voevoda, M. I., Maksimov, V. N., Orlov, Y. L., & Seregina, O. B. (2019) · BMC Medical Genomics · doi:10.1186/s12920-019-0484-9 · Cited by 44
“Assessment of biological significance of the detected mutations was carried out in the IARC TP53 Database and the TP53 UMD mutation database of human cancer [11, 12].”
MethodKang, E. Y., Cheasley, D. A., Page, C. L., Wakefield, M. J., Torres, M. D. C., Rowley, S. M., Salazar, C., Xing, Z., Allan, P. E., Bowtell, D. D. L., et al. (2020) · Modern Pathology · doi:10.1038/s41379-020-0618-9 · Cited by 42
Ripamonti, C. B., Colombo, M., Mondini, P., Manoukian, S., Peissel, B., Bernard, L., Radice, P., & Carcangiu, M. L. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-46 · Cited by 42
“This mutation was previously described in a case of Burkitt lymphoma [35].”
BackgroundTP53 Mutations in Canine Brain Tumors
York, D. S., Higgins, R. J., LeCouteur, R. A., WOLFE, A., Grahn, R. A., Olby, N. J., Campbell, M., & Dickinson, P. J. (2011) · Veterinary Pathology · doi:10.1177/0300985811424734 · Cited by 42
“Indirect methods, such as immunohistochemistry, may provide additional information regarding aberrant processing of p53 protein; however, it cannot distinguish among different types of mutations, does not detect truncating mutations, can be variable depending on operator and antibody used, and can give false-positive…”
BackgroundMethodInfluentialExpression and functions of galectin-7 in ovarian cancer
Labrie, M., Vladoiu, M. C., Grosset, A., Gaboury, L. A., & St‐Pierre, Y. (2014) · Oncotarget · doi:10.18632/oncotarget.2299 · Cited by 41
“In contrast, gal-7 was not detected in ovarian cancer cells harboring a wild-type p53 (A2780 and COV434 cells) or cells with a p53null genotype (e.g., SKOV-3) [13] Transfection of SK-OV-3 cells with expression vectors encoding p53 with mutations at codons 175, 273, and 248 all induced de novo expression of gal-7 at bo…”
InfluentialCell migration leads to spatially distinct but clonally related airway cancer precursors
Pipinikas, C., Kiropoulos, T. S., TEIXEIRA, V. H., Brown, J., Varanou, A., Falzon, M., Capitanio, A., Bottoms, S., Carroll, B., Navani, N., et al. (2014) · Thorax · doi:10.1136/thoraxjnl-2013-204198 · Cited by 38
Basak, D., Punganuru, S. R., & Srivenugopal, K. S. (2016) · International Journal of Oncology · doi:10.3892/ijo.2016.3372 · Cited by 41
“p53, also known as the guardian of the genome is found to be mutated in >50% of all human cancers and these mutations drive the emergence of oncogenic genomes and aggressive malignancies (6,7).”
BackgroundValente, L. J., Aubrey, B. J., Herold, M. J., Kelly, G. L., Happo, L., Scott, C. L., Newbold, A., Johnstone, R. W., Huang, D. C. S., Vassilev, L. T., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.059 · Cited by 40
“(A) Panel of selected human hematopoietic-cancer-derived cell lines with p53 status indicated, according to the International Agency for Research on Cancer (IARC) p53 database (Petitjean et al., 2007).”
BackgroundMethodInfluentialNon-coding RNAs, guardians of the p53 galaxy
Chen, S., Thorne, R. F., Zhang, X. D., Wu, M., & Liu, L. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.09.002 · Cited by 41
Zhang, J., Yu, G., Yang, Y., Wang, Y., Guo, M., Yin, Q., Yan, C., Tian, J., Fu, F., & Wang, H. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106128 · Cited by 43
p53 amyloid aggregation in cancer: function, mechanism, and therapy
Li, J., Guo, M., Chen, L., Chen, Z., Fu, Y., & Chen, Y. (2022) · Experimental Hematology and Oncology · doi:10.1186/s40164-022-00317-7 · Cited by 41
Brocke, J. V., Krais, A. M., Whibley, C. E., Hollstein, M. C., & Schmeiser, H. H. (2008) · Mutagenesis · doi:10.1093/mutage/gen049 · Cited by 41
“3-NBA treated 3NBA-J-253 ag to gg A to G Splice site 3NBA-J-131 CGC to CGA G to Tb R 72 Rc 1/16 (6, 3) 3NBA-J-246 cag to cat g to t Splice site 3NBA-J-256 CCT to CAT G to Tb P 128 H 0/28 (0, 0) 3NBA-J-135, -136, -145, -148 TAC to TGC A to G Y 163 C 179/255 (70, 2) 3NBA-J-134 GTG to TTG G to T V 173 L 67/205 (32, 6) 3N…”
BackgroundInfluentialStructural basis for p53 binding to its nucleosomal target DNA sequence
Nishimura, M., Takizawa, Y., Nozawa, K., & Kurumizaka, H. (2022) · PNAS Nexus · doi:10.1093/pnasnexus/pgac177 · Cited by 41
“Mutations in p53 have been found in about 50% of cancer patients, and most of the mutations are accumulated within the DBD (3, 4).”
BackgroundMerino, D. M., & Malkin, D. M. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_1 · Cited by 39
Fiore, R. D., Marcatti, M., Drago‐Ferrante, R., D’Anneo, A., Giuliano, M., Carlisi, D., BLASIO, A. D., Querques, F., Pastore, L., Tesoriere, G., et al. (2014) · Bone · doi:10.1016/j.bone.2013.12.021 · Cited by 40
Razorenova, O. V., Castellini, L., Colavitti, R., Edgington‐Mitchell, L. E., Nicolau, M., Huang, X., Bedogni, B., Mills, E., Bogyo, M. S., & Giaccia, A. J. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00644-12 · Cited by 40
“Since CC-RCC is highly aggressive and unresponsive to radiation and chemotherapy, there is a large interest in the field concerning the mechanism of this resistance, especially because p53 mutations are rarely detected in this type of cancer (49) (IARC p53 database [http://www-p53.”
BackgroundMolecular targeted therapies in metastatic melanoma
Comfere, N. I., Chakraborty, & Wieland, W. (2013) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s44800 · Cited by 41
“However, TP53 mutations represent a low frequency event in melanoma, occurring in only 9% of melanomas.(30) MDM2 is one of the negative regulators of p53 and is regulated by p14 (one of the protein products of CDKN2A) which, when bound to MDM2, inhibits its function and stabilizes p53.”
Kim, S. A., Kim, M.-S., Kim, M., Kim, S. C., Choi, J., Yu, E., & Hong, S. (2013) · Human Pathology · doi:10.1016/j.humpath.2013.08.016 · Cited by 40
“4%) was the second most common [34].”
Backgroundp53mutations associated with aging-related rise in cancer incidence rates
Richardson, R. B. (2013) · Cell Cycle · doi:10.4161/cc.25494 · Cited by 41
“IARC TP53 data for cancer sites was initially found by topography, whereas the TP53 data on principal tumors was found by their morphology.(3,61) Body mass index and cancer incidence data by country A non-TP53 influence, obesity, was briefly studied by use of agestandarized, mean body mass index (kg m) data by country…”
MethodSolomon, H., Brosh, R., Buganim, Y., & Rotter, V. (2010) · PubMed · Cited by 40
Identifying the determinants of response to MDM2 inhibition
Saiki, A. Y., Caenepeel, S. R., Cosgrove, E. J., Su, C., Boedigheimer, M. J., & Oliner, J. D. (2015) · Oncotarget · doi:10.18632/oncotarget.3116 · Cited by 39
Wang, Y., Xu, Y., Chen, J., Ouyang, T., Li, J., Wang, T., Fan, Z., Fan, T., Lin, B., & Xie, Y. (2015) · International Journal of Cancer · doi:10.1002/ijc.29715 · Cited by 39
“Moreover, TP53 is one of the most mutated genes in human cancers,(5) with a mutation rate of 30–40% in breast cancers.(6,7) TP53 mutations affect the transcriptional activity of TP53 protein(7) or even acquire new functions.”
BackgroundPu-erh Tea Inhibits Tumor Cell Growth by Down-Regulating Mutant p53
Zhao, L., Jia, S., Tang, W., Sheng, J., & Luo, Y. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12117581 · Cited by 39
“IARC TP53 database (version R14, November 2009) [10] shows that human p53N239S (or p.”
BackgroundNovello, C., Pazzaglia, L., Conti, A., Quattrini, I., Pollino, S., Perego, P., Picci, P., & Benassi, M. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114757 · Cited by 41
Fountzilas, G., Giannoulatou, E., Alexopoulou, Z., Zagouri, F., Timotheadou, E. T., Papadopoulou, K., Lakis, S., Bobos, M., Poulios, C., Sotiropoulou, M. G., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.9022 · Cited by 39
“Additionally, in line with the published literature [17, 36], the majority of mutations in both genes were missense.”
BackgroundResultp53 regulates cytoskeleton remodeling to suppress tumor progression
Araki, K., Ebata, T., Guo, A. K., Tobiume, K., Wolf, S. J., & Kawauchi, K. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1989-9 · Cited by 41
“Concomitantly, many p53 mutants have a simultaneous dominant-negative effect over wild-type p53 [46].”
BackgroundThe PTTG1-Binding Factor (PBF/PTTG1IP) Regulates p53 Activity in Thyroid Cells
Read, M. L., Seed, R., Fong, J. C., Modasia, B., Ryan, G. A., Watkins, R. J., Gagliano, T., Smith, V. E., Stratford, A. L., Kwan, P., et al. (2014) · Endocrinology · doi:10.1210/en.2013-1646 · Cited by 39
“regulator in maintaining genetic stability (13) and medi-”
Tumor-specific MAGE proteins as regulators of p53 function
Ladelfa, M. F., Peche, L. Y., Toledo, M. F., Laiseca, J. E., Schneider, C., & Monte, M. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.05.031 · Cited by 38
“More than 50% of human cancers harbor inactivating mutations on p53 [21].”
BackgroundSosin, A. M., Burger, A. M., Siddiqi, A., Abrams, J., Mohammad, R. M., & Al-Katib, A. M. (2012) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-5-57 · Cited by 40
“This is an attractive therapeutic strategy [22], particularly in lymphomas, where p53 mutations account for less than 15% of all cases [23,24], yet wt-p53 remains dysfunctional due to overexpressed HDM2.”
BackgroundBianchi-Frias, D., Basom, R., Delrow, J. J., Coleman, I. M., Dakhova, O., Qu, X., Fang, M., Franco, O. E., Ericson, N. G., Bielas, J. H., et al. (2016) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0330 · Cited by 38
Ikehata, H. (2018) · Photochemical & Photobiological Sciences · doi:10.1039/c7pp00360a · Cited by 38
Marečková, A., Malčíková, J., Tom, N., Pál, K., Radová, L., Šálek, D., Janíková, A., Moulis, M., Šmardová, J., Křen, L., et al. (2019) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2018.1542144 · Cited by 39
“according to database of the International Agency for Research on Cancer (IARC) [26].”
MethodInfluentialGhezelayagh, T. S., Pennington, K. P., Norquist, B. M., Khasnavis, N., Radke, M. R., Kilgore, M., Garcia, R. L., Lee, M. J., Katz, R., Leslie, K. K., et al. (2020) · Gynecologic Oncology · doi:10.1016/j.ygyno.2020.12.007 · Cited by 38
Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4
Burikhanov, R., Shrestha-Bhattarai, T., Hebbar, N., Qiu, S. G., Zhao, Y., Zambetti, G. P., & Rangnekar, V. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2013.12.020 · Cited by 41
“…up-or downregulation of transcriptional target genes involved in cell-cycle progression or apoptosis plays an important role in the tumor suppressor function of p53, it is not surprising that p53 is mutated within its DNA binding domain in a large number of human cancers (Petitjean et al., 2007).”
BackgroundInvolvement of activation-induced cytidine deaminase in skin cancer development
NONAKA, T., Toda, Y., Hiai, H., Uemura, M., Nakamura, M., Yamamoto, N., Asato, R., Hattori, Y., Bessho, K., Minato, N., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81522 · Cited by 37
“The current version of the IARC TP53 mutation database (22) contains a total of 88 cases of cutaneous SCC of the male and female external genitalia.”
Bobek, P., GINTER, E., Kuniak, Ľ., Babala, J., Jurcovicová, M., Ozdín, L., & Cerveń, J. (1991) · PubMed · Cited by 38
Laryngeal Cancer in the Modern Era: Evolving Trends in Diagnosis, Treatment, and Survival Outcomes
Hut, A.-R., Boia, E. R., Para, D. M., Iovănescu, G., Horhat, D. I., Mikša, L., Chiriac, M., Galant, R., Motofelea, A. C., & Balica, N. C. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14103367 · Cited by 44
Lee, S. K., Bae, S. Y., Lee, J. H., Lee, H., Yi, H., Kil, W. H., Lee, J. E., Kim, S. W., & Nam, S. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124658 · Cited by 37
“Overexpression of p53, which is caused by TP 53 mutation, is the most frequent genetic alteration in breast cancer [4, 5].”
BackgroundPhang, B. H., Othman, R., Bougeard, G., Chia, R. H., Frébourg, T., Tang, C. L., Cheah, P. Y., & Sabapathy, K. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510043112 · Cited by 37
Zhang, G., Xue, W.-B., An, Y.-F., Yuan, J., Qin, J., Pan, C., & Su, G. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.03.053 · Cited by 37
Deacetylation of the DNA-binding Domain Regulates p53-mediated Apoptosis
Mellert, H. S., Stanek, T. J., Sykes, S. M., Rauscher, F. J., Schultz, D., & McMahon, S. B. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.184663 · Cited by 37
Sanchez, J., DeJulius, K. L., Bronner, M. P., Church, J. M., & Kalady, M. F. (2011) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21526 · Cited by 37
“html).(25) Mutations in exon 8 were more common in sporadic cancers than in UC-associated cancers (53% versus 6%, P < 0.”
BackgroundAngst, E., Dawson, D. W., Nguyen, A., Park, J. R., Go, V. L. W., Reber, H. A., Hines, O. J., & Eibl, G. (2010) · Pancreas · doi:10.1097/mpa.0b013e3181c8b476 · Cited by 34
“Except for AsPc-1, which contains a p53 deletion with frameshift, the genetic alterations in the remaining cell lines are point mutations, which might differentially affect p53 function.(23) Another regulatory mechanism of NDRG1 expression is the myc family of protooncogenes.”
BackgroundMutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy
Houghton, J., Li, H., Fan, X., Liu, Y., Liu, J. H., Rao, V. P., Poutahidis, T., Taylor, C. L., Jackson, E. A., Hewes, C., et al. (2010) · Stem Cells and Development · doi:10.1089/scd.2009.0439 · Cited by 36
“Our model addresses the function of clinically relevant p53 mutations [ 20 ] in mesenchymal cells and their ability to initiate cancer in a tissue-specifi c fashion in an at-risk mammary carcinoma model.”
BackgroundMethodPreferential killing of p53-deficient cancer cells by reversine
Jèmaà, M., Galluzzi, L., Kepp, O., Boilève, A., Lissa, D., Senovilla, L., Harper, F., Pierron, G., Berardinelli, F., Antoccia, A., et al. (2012) · Cell Cycle · doi:10.4161/cc.20621 · Cited by 38
“worsened prognosis in a large spectrum of neoplasms.(13,14) Finally, both pharmacological and genetic strategies aimed at reconstituting the oncosuppressive functions of p53 have been shown to exert consistent anticancer effects in vivo in a wide array of preclinical models of neoplasia as well as in cancer patients p…”
BackgroundHow the environment shapes cancer genomes
Pfeifer, G. P. (2014) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000152 · Cited by 38
“Two major TP53 mutational databases containing tens of thousands of mutations have been established that summarize the types of mutations reported in the literature [6,7].”
BackgroundBulky DNA Adducts, Tobacco Smoking, Genetic Susceptibility, and Lung Cancer Risk
Munnia, A., Giese, R. W., Polvani, S., Galli, A., Cellai, F., & Peluso, M. E. M. (2017) · Advances in clinical chemistry · doi:10.1016/bs.acc.2017.01.006 · Cited by 37
Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis
Roszkowska, K. A., Giziński, S., Sady, M., Gajewski, Z., & Olszewski, M. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041334 · Cited by 37
“The various GOF phenotypes of certain mutations in p53, including early tumor onset, changed tumor spectrum, and increased propensity for metastasis were demonstrated in numerous transgenic mouse models beginning in 2000s [18–25] as well as in clinical molecular databases [26,27].”
BackgroundDietary Flavonoids in p53—Mediated Immune Dysfunctions Linking to Cancer Prevention
Siddiqui, S. S., Rahman, S., Rupasinghe, H. P. V., & Vazhappilly, C. G. (2020) · Biomedicines · doi:10.3390/biomedicines8080286 · Cited by 36
“Further experiments strengthen the notion that the wild type p53 can suppress oncogenic transformation [9].”
BackgroundLi, H., Cai, Q., Yan, X., & Jie, G. (2021) · Nanoscale · doi:10.1039/d1nr00573a · Cited by 37
Ono, W., Hayashi, Y., Yokoyama, W., Kuroda, T., Kishimoto, H., Ito, I., Kimura, K., Akaogi, K., Waku, T., & Yanagisawa, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.474049 · Cited by 39
Zainuddin, N., Berglund, M., Wanders, A., Ren, Z.-P., Amini, R., Lindell, M., Kanduri, M., Roos, G., Rosenquist, R., & Enblad, G. (2008) · Leukemia Research · doi:10.1016/j.leukres.2008.06.022 · Cited by 37
Hereditary Diffuse Gastric Cancer
Schrader, K. A., & Huntsman, D. D. (2010) · Cancer treatment and research · doi:10.1007/978-1-4419-6033-7_3 · Cited by 36
Falisi, E., Novella, E., Visco, C., Guercini, N., Maura, F., Giaretta, I., Pomponi, F., Nichele, I., Finotto, S., Montaldi, A., et al. (2013) · Hematological Oncology · doi:10.1002/hon.2086 · Cited by 36
Yang, Y., Xia, T., Li, N., Zhang, J., Yang, Y., Cong, W., Deng, Q., Lan, K., & Zhou, W. (2012) · Protein & Cell · doi:10.1007/s13238-012-2067-9 · Cited by 36
“Somatic mutation of p53 is found in 32% of all human liver tumor cases (Petitjean et al., 2007).”
BackgroundSagne, C., Marcel, V., Bota, M., Martel‐Planche, G., Nóbrega, A., Palmero, E., Perriaud, L., Boniol, M., Vagner, S., Cox, D., et al. (2014) · Carcinogenesis · doi:10.1093/carcin/bgt381 · Cited by 33
Self-citationPatties, I., Kortmann, R., Menzel, F., & Glasow, A. (2016) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0376-1 · Cited by 36
“DAOY cells are TP53-mutated, whereas MEB-Med8a and D283-Med cell lines are wild-type TP53 [29, 30].”
BackgroundLiu, H., Li, J., Zhou, Y., Hu, Q., Zeng, Y., & Mehryar, M. M. (2016) · Journal of Medical Virology · doi:10.1002/jmv.24670 · Cited by 36
“Moreover, mutations in p53 genes coding for p53 proteins were observed in most of cancers as result of exposure to alcohol or tobacco [Benhattar et al., 1996; Lenz et al., 1998; Obata et al., 2000; Petitjean et al., 2007].”
BackgroundMoussa, R., Park, K. C., Kovačević, Ž., & Richardson, D. R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.03.027 · Cited by 39
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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