Journal ArticleDOI
Hypermutability in Carcinogenesis
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TLDR
The published data indicate that TP53 is hypermutable at some stage of tumor development, and it is not yet clear whether TP 53 is unique or whether other genes display a similar pattern of silent and multiple mutations.Abstract:
The presence of numerous chromosomal changes and point mutations in tumors is well established. At least some of these changes play a role in the development of the tumors. It has been suggested that the number of these genetic changes requires that tumorigenesis involves an increase in mutation rate. However, the presence of numerous changes can also be accounted for by efficient selection. What is required to settle the issue is some measure of nonselected mutations in tumors. In order to determine whether the tumor suppressor TP53 (coding for the protein p53) is hypermutable at some stage of carcinogenesis, the frequency of silent and multiple mutations in this gene has been examined. Silent mutations make up approximately 3% of the total recorded but constitute 9.5% of the mutations found in tumors with multiple mutations. Multiple closely linked mutations are also observed. Such multiple mutations suggest the operation of an error-prone replication process in a subclass of cells. The published data indicate that TP53 is hypermutable at some stage of tumor development. It is not yet clear whether TP53 is unique or whether other genes display a similar pattern of silent and multiple mutations.read more
Citations
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Book ChapterDOI
p53 and human cancer: the first ten thousand mutations.
Pierre Hainaut,Monica Hollstein +1 more
TL;DR: The chapter describes a three-step model of pS3 activation by stress signals and concludes with the potential clinical applications of the detection of p53 mutations in human tissues.
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Dynamics of cancer progression
TL;DR: The fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells are revealed.
Journal ArticleDOI
Patterns of p53 G-->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke.
Pierre Hainaut,Gerd P. Pfeifer +1 more
TL;DR: The p53 mutation spectra are different between smokers and non-smokers and that this difference is highly statistically significant, reinforcing the notion that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.
Journal ArticleDOI
Genetic pathways in colorectal and other cancers
TL;DR: This review examines colorectal cancer as a classical example of multistep carcinogenesis and examines the mutations that comprise these pathways and the possible functional sequelae of these are explored.
Journal ArticleDOI
The SOS response regulates adaptive mutation
Gregory J. McKenzie,Reuben S. Harris,Reuben S. Harris,Peter L. Lee,Susan M. Rosenberg,Susan M. Rosenberg +5 more
TL;DR: It is shown that adaptive mutation is regulated by the SOS response, a complex, graded response to DNA damage that includes induction of gene products blocking cell division and promoting mutation, recombination, and DNA repair.
References
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Journal ArticleDOI
Conditional Mutator Phenotypes in hMSH2-Deficient Tumor Cell Lines
TL;DR: Two human tumor cell lines that are deficient in the mismatch repair protein hMSH2 show little or no increase in mutation rate relative to that of a mismatch repair-proficient cell line when the cells are maintained in culture conditions allowing rapid growth, but mutations accumulate at a high rate when they are maintained at high density.
Book ChapterDOI
The natural somatic mutation frequency and human carcinogenesis.
TL;DR: The data suggest that somatic mutation in human epithelial cells may be some 10-fold higher than in peripheral blood lymphocytes and that the underlying rate of spontaneous mutation is sufficient to account for a large proportion of human carcinogenesis without the need to evoke either stepwise alteration to a mutator phenotype of clonal expansion at all the mutation steps in carcinogenesis.
Journal Article
Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy.
Kyoko Takayama,Edmund P. Salazar,Bernard C. Broughton,Alan R. Lehmann,Alain Sarasin,Larry H. Thompson,Christine A. Weber +6 more
TL;DR: Nucleotide-sequence analysis of the ERCC2 cDNA from three TTD cell strains revealed mutations within the region from amino acid 713-730 and within previously identified helicase functional domains that can be correlated with the various clinical presentations and DNA repair characteristics of the cell strains.
Journal ArticleDOI
Mutations of the Transforming Growth Factor-β Type II Receptor Gene and Genomic Instability in Hereditary Nonpolyposis Colorectal Cancer
TL;DR: The data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.
Journal ArticleDOI
Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: a meta-analysis.
Ainsley Weston,James Godbold +1 more
TL;DR: The results of a metaanalysis, which reviews studies of H-ras-1 rare alleles and p53 codon 72 allelic variants in breast and lung cancer, are presented and there is evidence for elevated risk of both breast and Lung cancer with inheritance of rare H-ra-1 alleles.