New approaches to understanding p53 gene tumor mutation spectra.

The first p53 gene mutation arising in a human tumor was described a decade ago by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C. Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura, R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas, Science 244 (1989) 217-221]. There are now over 10,000 mutations extracted from the published literature in the IARC database of human p53 tumor mutations [P. Hainaut, T. Hernandez, A. Robinson, P. Rodriguez-Tome, T. Flores, M. Hollstein, C.C. Harris, R. Montesano, IARC database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualization tools, Nucleic Acids Res. 26 (1998) 205-213; Version R3, January 1999]. A large and diverse collection of tumor mutations in cancer patients provides important information on the nature of environmental factors or biological processes that are important causes of human gene mutation, since xenobiotic mutagens as well as endogenous mechanisms of genetic change produce characteristic types of patterns in target DNA [J.H. Miller, Mutational specificity in bacteria, Annu. Rev. Genet. 17 (1983) 215-238; T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362 (1993) 709-715; S.P. Hussain, C.C. Harris, Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes, Cancer Res. 58 (1998) 4023-4037; P. Hainaut, M. Hollstein, p53 and human cancer: the first ten thousand mutations, Adv. Cancer Res. 2000]. P53 gene mutations in cancers can be compared to point mutation spectra at the HPRT locus of human lymphocytes from patients or healthy individuals with known exposure histories, and accumulated data indicate that mutation patterns at the two loci share certain general features. Hypotheses regarding specific cancer risk factors can be tested by comparing p53 tumor mutations typical of a defined patient group against mutations generated experimentally in rodents or in prokaryotic and eukaryotic cells in vitro. Refinements of this approach to hypothesis testing are being explored that employ human p53 sequences introduced artificially into experimental organisms used in laboratory mutagenesis assays. P53-specific laboratory models, combined with DNA microchips designed for high through-put mutation screening promise to unmask information currently hidden in the compilation of human tumor p53 mutations.

[1]  M. You,et al.  Dose-dependent ras mutation spectra in N-nitrosodiethylamine induced mouse liver tumors and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced mouse lung tumors. , 1993, Carcinogenesis.

[2]  Harris Cc,et al.  Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. , 1998 .

[3]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[4]  A. Inga,et al.  Ultraviolet-light induced p53 mutational spectrum in yeast is indistinguishable from p53 mutations in human skin cancer. , 1998, Carcinogenesis.

[5]  M. You,et al.  Effect of green tea on p53 mutation distribution in ultraviolet B radiation-induced mouse skin tumors. , 1998, Carcinogenesis.

[6]  E. Newcomb,et al.  p53 mutations in C57BL/6J murine thymic lymphomas induced by gamma-irradiation and N-methylnitrosourea. , 1992, Cancer research.

[7]  P. Hainaut,et al.  Mutation spectra resulting from carcinogenic exposure: from model systems to cancer-related genes. , 1998, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[8]  J. Miller,et al.  Proliferation of mutators in A cell population , 1997, Journal of bacteriology.

[9]  M. Miller,et al.  Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene. , 1998, Carcinogenesis.

[10]  C. Harris,et al.  Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. , 1994, Cancer research.

[11]  K. Miyagawa,et al.  p53 Gene Mutation and Loss of Heterozygosity of Chromosome 11 in Methylcholanthrene‐induced Mouse Sarcomas , 1998, Japanese Journal of Cancer Research : Gann.

[12]  K. Bhatia,et al.  Infrequent p53 mutation in mouse tumors with deregulated myc. , 1992, Cancer research.

[13]  J. Roth,et al.  Ki‐ras and p53 mutations are early and late events, respectively, in urethane‐induced pulmonary carcinogenesis in A/J mice , 1996, Molecular carcinogenesis.

[14]  G. Holmquist,et al.  Somatic mutation theory, DNA repair rates, and the molecular epidemiology of p53 mutations. , 1997, Mutation research.

[15]  C. Sutter,et al.  Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. , 1992, Cancer research.

[16]  R. Iggo,et al.  A rapid PCR fidelity assay. , 1994, Nucleic acids research.

[17]  J. Broach,et al.  p53 mutations isolated in yeast based on loss of transcription factor activity: similarities and differences from p53 mutations detected in human tumors , 1998, Oncogene.

[18]  R. Storer,et al.  Murine p53 intron sequences 5–8 and their use in polymerase chain reaction/direct sequencing analysis of p53 mutations in CD‐1 mouse liver and lung tumors , 1992, Molecular carcinogenesis.

[19]  S. Fukushima,et al.  LOH and mutational analysis of p53 alleles in mouse urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. , 1999, Carcinogenesis.

[20]  A. Gough,et al.  p53 is not inactivated in B6C3F1 mouse vascular tumors arising spontaneously or associated with long-term administration of the thiazolidinedione troglitazone. , 1999, Toxicology and applied pharmacology.

[21]  S. Seité,et al.  p53 mutations in cutaneous lesions induced in the hairless mouse by a solar ultraviolet light simulator , 1998, Molecular carcinogenesis.

[22]  P. Hainaut,et al.  Hepatocellular carcinoma: from gene to public health. , 1997, Journal of the National Cancer Institute.

[23]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[24]  S. Antal,et al.  Carcinogenic alterations in murine liver, lung, and uterine tumors induced by in utero exposure to ionizing radiation , 1998, Molecular carcinogenesis.

[25]  A. de Vries,et al.  Frequent p53 alterations but low incidence of ras mutations in UV-B-induced skin tumors of hairless mice. , 1995, Carcinogenesis.

[26]  M. Hegi,et al.  Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice. , 1993, Carcinogenesis.

[27]  W. Pierceall,et al.  High frequency of p53 mutations in ultraviolet radiation-induced murine skin tumors: evidence for strand bias and tumor heterogeneity. , 1993, Cancer research.

[28]  H. Yonekawa,et al.  Mutational and LOH analyses of p53 alleles in colon tumors induced by 1,2-dimethylhydrazine in F1 hybrid mice. , 1995, Carcinogenesis.

[29]  M. Smith,et al.  Chronic ultraviolet exposure-induced p53 gene alterations in Sencar mouse skin carcinogenesis model. , 1997, Journal of toxicology and environmental health.

[30]  T. Goodrow,et al.  Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Rumsby,et al.  Screening for p53 mutations in c3h/he mouse liver tumors derived spontaneously or induced with diethylnitrosamine or phenobarbitone , 1994, Molecular carcinogenesis.

[32]  L. Donehower,et al.  Infrequent p53 mutations in 7,12‐dimethylbenz[a]anthracene–induced mammary tumors in BALB/c and p53 hemizygous mice , 1994, Molecular carcinogenesis.

[33]  N F Cariello,et al.  Software for the analysis of mutations at the human hprt gene. , 1994, Mutation research.

[34]  M. Tatematsu,et al.  Frequent mutations of the p53 gene and infrequent H- and K-ras mutations in urinary bladder carcinomas of NON/Shi mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. , 1995, Carcinogenesis.

[35]  S. Leone‐Kabler,et al.  Role of tumor suppressor genes in transplacental lung carcinogenesis , 1998, Molecular carcinogenesis.

[36]  R W Wallace.  DNA on a chip: serving up the genome for diagnostics and research. , 1997, Molecular medicine today.

[37]  W. El-Deiry,et al.  Regulation of p53 downstream genes. , 1998, Seminars in cancer biology.

[38]  J. Rossant,et al.  Genome engineering: the new mouse genetics , 1995, Nature Medicine.

[39]  D. Medina,et al.  Expression of a p53 mutant in the epidermis of transgenic mice accelerates chemical carcinogenesis , 1998, Oncogene.

[40]  S. Fukushima,et al.  High susceptibility of p53(+/-) knockout mice in N-butyl-N-(4-hydroxybutyl)nitrosamine urinary bladder carcinogenesis and lack of frequent mutation in residual allele. , 1998, Cancer research.

[41]  T. Devereux,et al.  Predominant p53 G→A Transition Mutation and Enhanced Cell Proliferation in Uterine Sarcomas of CBA Mice Treated with 1,2-Dimethylhydrazine , 1998, Toxicologic pathology.

[42]  T. Tamaya,et al.  Rare occurrence of p53 and ras gene mutations in preneoplastic and neoplastic mouse endometrial lesions induced by N-methyl-N-nitrosourea and 17 beta-estradiol. , 1995, Cancer letters.

[43]  B. Strauss.  Hypermutability and silent mutations in human carcinogenesis. , 1998, Seminars in cancer biology.

[44]  C. Weghorst,et al.  Lack of p53 and ras mutations in Helicobacter hepaticus-induced liver tumors in A/JCr mice. , 1997, Carcinogenesis.

[45]  S. Fukushima,et al.  Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine. , 1999, Cancer Letters.

[46]  M. Hattori,et al.  Rare Occurrence of ras and p53 Gene Mutations in Mouse Stomach Tumors Induced by N–Methyl–N–nitrosourea , 1997, Japanese journal of cancer research : Gann.

[47]  M. S. St John,et al.  Frequent p53 mutations and occasional loss of chromosome 4 in invasive bladder carcinoma induced by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine in B6D2F1 mice , 1998, Molecular carcinogenesis.

[48]  B. Parsons,et al.  Detection of basepair substitution mutation at a frequency of 1 × 10−7 by combining two genotypic selection methods, MutEx enrichment and allele‐specific competitive blocker PCR , 1998, Environmental and molecular mutagenesis.

[49]  S. Fukushima,et al.  Possible rare involvement of O6-methylguanine formation as a significant mutational factor in mouse urinary bladder carcinogenesis models. , 1998, Teratogenesis, carcinogenesis, and mutagenesis.

[50]  G. Wogan,et al.  UV-induced mutagenesis of human p53 in a vector replicated in Saccharomyces cerevisiae. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Patricia Rodriguez-Tomé,et al.  IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools , 1998, Nucleic Acids Res..

[52]  V. Steele,et al.  K-ras mutations in lung tumors from A/J and A/J x TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate. , 1995, Carcinogenesis.

[53]  M. Kripke,et al.  Sunlight and skin cancer: Inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens , 1997, Nature Medicine.

[54]  C. Weghorst,et al.  Lack of p53 point mutations in chemically induced mouse hepatoblastomas: an end-stage, highly malignant hepatocellular tumor. , 1995, Cancer letters.

[55]  Y. Hosoya,et al.  Mutation, loss of heterozygosity, and recombination of the p53 gene in mouse forestomach tumors induced by 2‐amino‐3,4‐dimethylimidazo[4,5‐f]quinoline , 1995, Molecular carcinogenesis.

[56]  K. Rajewsky,et al.  Conditional gene targeting. , 1996, The Journal of clinical investigation.

[57]  H. Ohgaki,et al.  Induction of hepatocellular carcinoma and highly metastatic squamous cell carcinomas in the forestomach of mice by feeding 2-amino-3,4-dimethylimidazo[4,5-f]quinoline. , 1986, Carcinogenesis.

[58]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.

[59]  Webster K. Cavenee,et al.  Pathology and genetics of tumours of the nervous system. , 2000 .

[60]  M. Tang,et al.  Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53 , 1996, Science.

[61]  T. Goodrow,et al.  Lack of concordant p53 mutations in some paired primary and metastatic mouse squamous cell carcinomas induced by chemical carcinogenesis , 1995, Molecular carcinogenesis.

[62]  B. Lambert,et al.  Spectrum of point mutations in the coding region of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene in human T-lymphocytes in vivo. , 1998, Carcinogenesis.

[63]  N. Dumaz,et al.  The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice. , 1997, Carcinogenesis.

[64]  P. Chappuis,et al.  A simple p53 functional assay for screening cell lines, blood, and tumors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[65]  P. Jeffrey,et al.  Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. , 1994, Science.

[66]  J. Brickmann,et al.  On the origins of tumor mutations in cancer genes: insights from the p53 gene. , 1998, Mutation research.

[67]  M. Evans,et al.  p53 modulation of TFIIH–associated nucleotide excision repair activity , 1995, Nature Genetics.

[68]  J. Schweizer,et al.  p53 mutations are absent from carcinogen‐induced mouse liver tumors but occur in cell lines established from these tumors , 1992, Molecular carcinogenesis.

[69]  C. Prives,et al.  Human tumor-derived p53 proteins exhibit binding site selectivity and temperature sensitivity for transactivation in a yeast-based assay , 1998, Oncogene.

[70]  E. Campo,et al.  Ki‐ras gene mutations and absence of p53 gene mutations in spontaneous and urethane‐induced early lung lesions in CBA/J mice , 1998, Molecular carcinogenesis.

[71]  T. Soussi,et al.  Structural aspects of the p53 protein in relation to gene evolution. , 1990, Oncogene.

[72]  L. Loeb,et al.  Mutator phenotype may be required for multistage carcinogenesis. , 1991, Cancer research.

[73]  M. Tatematsu,et al.  Clonal analysis of urothelial carcinomas in C3H/HeN<-->BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. , 1998, Carcinogenesis.

[74]  G. Jenkins,et al.  Enhanced restriction site mutation (RSM) analysis of 1,2-dimethylhydrazine induced mutations, using endogenous p53 intron sequences. , 1997, Mutagenesis.

[75]  C. Harris,et al.  Geographic variation of p53 mutational profile in nonmalignant human liver. , 1994, Science.

[76]  R. Mangues,et al.  Absence of MDM‐2 gene amplification in experimentally induced tumors regardless of p53 status , 1994, Molecular carcinogenesis.

[77]  M. Tatematsu,et al.  Genetic instability and p53 mutations in metastatic foci of mouse urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. , 1997, Carcinogenesis.

[78]  N. Dumaz,et al.  Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Marshall W. Anderson,et al.  Comparison of pulmonary O6‐methylguanine dna adduct levels and Ki‐ras activation in lung tumors from resistant and susceptible mouse strains , 1993, Molecular carcinogenesis.

[80]  T. Jacks,et al.  Sunburn and p53 in the onset of skin cancer , 1994, Nature.

[81]  A. Klein-Szanto,et al.  Alterations of the p53 tumor suppressor gene during mouse skin tumor progression. , 1991, Cancer research.