Significance of TP53 mutations in human cancer: A critical analysis of mutations at CpG dinucleotides

A detailed analysis of p53 (TP53) mutations involving the 42 CpG dinucleotides was performed to gain greater insight into the mutational mechanism leading to specific selection of these mutations. Although the majority of these CpG dinucleotides have been found to be mutated in cancer cells, the heterogeneous frequency of mutational events suggests that some mutations are not true mutations, but neutral changes that have been co‐selected during oncogenic transformation. Among the 1,400 variants found in the 15,000 mutations of the p53 database, 5% have only been described once, indicating that either the mutational event is rare, or the mutation phenotype is very mild, or both. Overall, these data indicate that great caution is required when analyzing the significance of p53 mutations. Hum Mutat 21:192–200, 2003. © 2003 Wiley‐Liss, Inc.

[1]  Thierry Soussi,et al.  The UMD‐p53 database: New mutations and analysis tools , 2003, Human mutation.

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

[3]  Moshe Oren,et al.  The p53 and Mdm2 families in cancer. , 2002, Current opinion in genetics & development.

[4]  C. Junien,et al.  Mutations of the VHL gene in sporadic renal cell carcinoma: Definition of a risk factor for VHL patients to develop an RCC , 1999, Human mutation.

[5]  D. Green,et al.  Regional analysis of p53 mutations in rheumatoid arthritis synovium , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Francis S. Collins,et al.  Positional cloning moves from perditional to traditional , 1995, Nature Genetics.

[7]  B. Pasini,et al.  Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease , 1994, Nature.

[8]  C. Prives,et al.  A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis , 1996, Molecular and cellular biology.

[9]  S. Douc-Rasy,et al.  TP53 family members and human cancers , 2003, Human mutation.

[10]  D. Bowden,et al.  Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. , 1994, Human molecular genetics.

[11]  Thierry Soussi,et al.  TP53 tumor suppressor gene: A model for investigating human mutagenesis , 1992, Genes, chromosomes & cancer.

[12]  G. Thomas,et al.  Alleles of the APC gene: An attenuated form of familial polyposis , 1993, Cell.

[13]  R. Hofstra,et al.  A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma , 1994, Nature.

[14]  C. Harris,et al.  Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. , 1995, Oncogene.

[15]  H. Kazazian,et al.  VARIATION, DATABASES, and DISEASE: New directions for Human Mutation , 2000, Human mutation.

[16]  S. Hussain,et al.  p53 Tumor Suppressor Gene: At the Crossroads of Molecular Carcinogenesis, Molecular Epidemiology, and Human Risk Assessment , 2000, Annals of the New York Academy of Sciences.

[17]  K. Vousden Activation of the p53 tumor suppressor protein. , 2002, Biochimica et biophysica acta.

[18]  J. Varley,et al.  Characterization of germline TP53 splicing mutations and their genetic and functional analysis , 2001, Oncogene.

[19]  B. Vogelstein,et al.  Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the "hot spot" mutant phenotypes. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[20]  M. Tang,et al.  Cytosine methylation determines hot spots of DNA damage in the human P53 gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[22]  G. Pfeifer,et al.  Involvement of 5-methylcytosine in sunlight-induced mutagenesis. , 1999, Journal of molecular biology.

[23]  T. Soussi,et al.  Analysis of the most representative tumour‐derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. , 1994, The EMBO journal.

[24]  A. Levine,et al.  Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy , 1999, Oncogene.

[25]  B. Ponder,et al.  Mutations of the RET proto-oncogene in Hirschsprung's disease , 1994, Nature.

[26]  G. Lozano,et al.  Disrupting TP53 in mouse models of human cancers , 2003, Human mutation.

[27]  Thierry Soussi,et al.  Assessing TP53 status in human tumours to evaluate clinical outcome , 2001, Nature Reviews Cancer.

[28]  T. Soussi Focus on the p53 gene and cancer: Advances in TP53 mutation research , 2003, Human mutation.

[29]  T. Soussi,et al.  Splice mutations in the p53 gene: case report and review of the literature , 2003, Human mutation.

[30]  B. Ponder,et al.  Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A , 1993, Nature.

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

[32]  G. Thomas,et al.  Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients , 1993, Cell.

[33]  S. Tornaletti,et al.  Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. , 1995, Oncogene.

[34]  C. Harris,et al.  p53 mutation spectrum and load: the generation of hypotheses linking the exposure of endogenous or exogenous carcinogens to human cancer. , 1999, Mutation research.

[35]  Yubo Sun,et al.  p53, proto-oncogene and rheumatoid arthritis. , 2002, Seminars in arthritis and rheumatism.

[36]  R. Cotton,et al.  Mutation detection 2001: Novel technologies, developments and applications for analysis of the human genome , 2002 .

[37]  M. Oren,et al.  Specific loss of apoptotic but not cell‐cycle arrest function in a human tumor derived p53 mutant. , 1996, The EMBO journal.

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

[39]  Ourania Horaitis,et al.  Time for a unified system of mutation description and reporting: a review of locus-specific mutation databases. , 2002, Genome research.

[40]  J Soudon,et al.  Inactivation of the p53 gene expression by a splice donor site mutation in a human T-cell leukemia cell line. , 1991, Leukemia.

[41]  S. Lowe,et al.  Clinical implications of p53 mutations , 1999, Cellular and Molecular Life Sciences CMLS.

[42]  V. Ingram,et al.  A Specific Chemical Difference Between the Globins of Normal Human and Sickle-Cell Anæmia Hæmoglobin , 1956, Nature.