Hypermutability in Carcinogenesis
TL;DR: 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.
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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.
Abstract: Publisher Summary The p53 protein is a tight, hydrophobic central globule containing the DNA binding domain, flanked by accessible N- and C-terminal regions This protein is expressed in all cell types but has a rapid turnover and is latent under normal conditions p53 is mutated in most common human malignancies and behaves as a multifunctional transcription factor involved in the control of cell cycle, programmed cell death, senescence, differentiation and development, transcription, DNA replication, DNA repair, and maintenance of genomic stability p53 is converted to an active form in response to a number of physical or chemical DNA-damaging agents such as X or gamma irradiation, UV rays, oxidizing agents, cytotoxic drugs, and cancer-causing chemicals Induction of p53 implies nuclear retention, accumulation of the protein as a result of post-translational stabilization, and allosteric conversion to a form with high sequence-specific DNA-binding capacity p53 is activated in response to DNA damage, thus acting as a “guardian of the genome” against genotoxic stress The chapter describes a three-step model of pS3 activation by stress signals The downstream pS3 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins The mutations and variations in the p53 gene are due to p53 polymorphisms, somatic mutations, and germline mutations in p53 The chapter also accounts for p53 mutations in sporadic cancers focussing on host-environment interactions The chapter concludes with the potential clinical applications of the detection of p53 mutations in human tissues
976 citations
TL;DR: The fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells are revealed.
Abstract: Evolutionary concepts such as mutation and selection can be best described when formulated as mathematical equations. Cancer arises as a consequence of somatic evolution. Therefore, a mathematical approach can be used to understand the process of cancer initiation and progression. But what are the fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells? Also, how does a quantitative theory of somatic mutation and selection help us to evaluate the role of genetic instability?
462 citations
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.
Abstract: It is unquestionable that the major cause of lung cancer is cigarette smoking p53 mutations are common in lung cancers from smokers but less common in non-smokers A large fraction of the p53 mutations in lung cancers are G-->T transversions, a type of mutation that is infrequent in other tumors aside from hepatocellular carcinoma Previous studies have indicated that there is a good correlation between G-->T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon (PAH) adducts along the p53 gene The origin of p53 mutations in lung cancer has been questioned by recent reports suggesting that there are no significant differences in p53 mutation spectra between smokers and non-smokers and between lung cancers and non-lung cancers [SN Rodin and AS Rodin (2000) Human lung cancer and p53: The interplay between mutagenesis and selection P:roc Natl Acad Sci USA, 97, 12244-12249] We have re-assessed these issues by using the latest update of the p53 mutation database of the International Agency for Research on Cancer (14 051 entries) as well as recent data from the primary literature on non-smokers We come to the conclusion that the p53 mutation spectra are different between smokers and non-smokers and that this difference is highly statistically significant (G-->T transversions are 30 versus 10%; P T transversions in lung cancers but are almost exclusively G-->A transitions in non-lung cancers Our data reinforce 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
381 citations
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.
315 citations
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.
Abstract: Upon starvation some Escherichia coli cells undergo a transient, genome-wide hypermutation (called adaptive mutation) that is recombination-dependent and appears to be a response to a stressful environment. Adaptive mutation may reflect an inducible mechanism that generates genetic variability in times of stress. Previously, however, the regulatory components and signal transduction pathways controlling adaptive mutation were unknown. Here we show 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. We find that SOS-induced levels of proteins other than RecA are needed for adaptive mutation. We report a requirement of RecF for efficient adaptive mutation and provide evidence that the role of RecF in mutation is to allow SOS induction. We also report the discovery of an SOS-controlled inhibitor of adaptive mutation, PsiB. These results indicate that adaptive mutation is a tightly regulated response, controlled both positively and negatively by the SOS system.
255 citations
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TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
7,653 citations
TL;DR: It is found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas, which are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumors.
Abstract: Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.
6,309 citations
"Hypermutability in Carcinogenesis" refers background in this paper
...…as they progress, and it seems very likely that at least a portion of these genetic alterations play that diminish normal cellular surveillance mechanisms and increase the spontaneous mutation rate (Loeb 1994).a role in the etiology of the disease (Vogelstein et al. 1988; Goyette et al. 1992)....
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Book•
01 Jan 2006
TL;DR: Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in proKaryote Mutagenisation in eukaryotes Other DNA damage tolerance responses in eUKaryotes.
Abstract: DNA damage Mutations The reversal of base damage Base excision repair Nucleotide excision repair in prokaryotes Nucleotide excision repair in lower eukaryotes Nucleotide excision repair in mammalian cells: general considerations and chromatin dynamics Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in prokaryotes Mutagenesis in eukaryotes Other DNA damage tolerance responses in eukaryotes Hereditary diseases with defective responses to DNA damage
5,297 citations
TL;DR: Data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with H NPCC suggest that hMSH2 is the HNPCC gene.
2,763 citations
"Hypermutability in Carcinogenesis" refers background in this paper
...…is the association of certain colon carcinomas with defects in the mismatchare of different kinds and include both point mutations and qualitative and quantitative chromosome alter- repair genes (Fishel et al. 1993; Modrich 1995), but the earlier association of a defect in excision repairations....
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