DNA base changes and alkylation following in vivo exposure of Escherichia coli to N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea.

Richardson, Katherine; Richardson, Frank C.; Crosby, Renae M.; Swenberg, James A.; Skopek, Thomas R.

doi:10.1073/pnas.84.2.344

Cited by 196 publications

(104 citation statements)

References 40 publications

(43 reference statements)

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“…For instance, it could direct the search for carcinogens present in the diet or in cigarette smoke. The similarities in the spectra of ras mutations found in lung tumors and those induced by aromatic hydrocarbons such as benzopyrene (47) and in gastrointestinal tumors with those induced by alkylating agents such as methylnitrosourea (48) are certainly very suggestive.…”

Section: Discussionmentioning

confidence: 92%

Frequency and Spectrum of Mutations at Codons 12 and 13 of the C-K-ras Gene in Human Tumors

Capellà¹,

Cronauer-Mitra²,

Peinado³

et al. 1991

Environmental Health Perspectives

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The frequency of point mutations at codons 12 and 13 of the c-K-ras gene has been determined in a panel of more than 400 human tumors. Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas (n = 84); 40% of adenomas (n = 72) and carcinomas (n = 244) of the colon and rectum; 30% of carcinomas of the bile duct (n = 19); 25% of carcinomas of the lung (n = 92), and in lower frequency in other carcinomas, including liver, stomach, and kidney. No mutations were found in carcinomas of the breast, prostate, esophagus, and gall bladder, among others. Comparative analysis of the spectrum of mutations show that while G to A transitions were the most frequent mutations in pancreatic and colo-rectal tumors, G to T transversions were more prevalent in lung carcinomas. The aspartic acid mutation at codon 13 (GGC -* GAC) was relatively frequent in colo-rectal tumors but rare in pancreatic and lung carcinomas. The differences in the mutation spectrum of the c-K-ras gene in cancers of the gastrointestinal and respiratory tracts are suggestive of differential exposure to genotoxic agents.

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Section: Discussionmentioning

confidence: 92%

Frequency and Spectrum of Mutations at Codons 12 and 13 of the C-K-ras Gene in Human Tumors

Capellà¹,

Cronauer-Mitra²,

Peinado³

et al. 1991

Environmental Health Perspectives

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“…These di erences might be related to the type of induced genetic alteration. While MNU usually produces point mutations and alkylation in the DNA (Richardson et al, 1987), radiation can cause di erent kinds of DNA damage, including base alterations, deletions, insertions and internal rearrangements (Hutchinson, 1985). In concordance with this, although g-radiation-induced lymphomas are frequently deleted in a chromosome 4 region named TLSR1, no LOH in this region has been found in tumors induced by MNU treatment (Santos et al, 1996).…”

Section: Mouse P15 Ink4b and P16 Ink4a Cpg Islands Are Hypermethylatementioning

confidence: 93%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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A wide panel of murine induced T-cell lymphomas have been analysed for p16 INK4a or p15 INK4b alterations. Only one g-radiation-induced lymphoma showed p16 INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15 INK4b and p16 INK4a genes was found to be highly frequent. While p16 INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gradiation-induced lymphomas, de novo methylation of p15 INK4b occurs in 88% and 42% of these tumors respectively, correlating with de®cient expression of the corresponding mRNA and allelic losses in the p15 INK4b and p16 INK4a chromosome location. These data represent, to our knowledge, the ®rst report on the signi®cant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15 INK4b gene inactivation and support a tumor suppressor role for p15 INK4b in T-cell lymphomas independent of p16 INK4a .

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“…At both loci, the incidence and the location of GC4AT transitions are consistent with the hypothesis that O6-alkylguanine is the main determinant of CCNU mutagenicity. Alkylnitrosoureas preferentially cause GC4AT transitions at Gs preceded by a Pu residue in E. coli (Jurado et al, 1995;RoldaÁ n-Arjona et al, 1994;Richardson et al, 1987;Burns et al, 1988) and in eukaryotes (Inga et al, 1995;Kunz and Mis, 1989;Minnick et al, 1992;Moriwaki et al, 1991;Palombo et al, 1992). The 5'-¯anking purine eect has been explained as the consequence of a structural in¯uence on the initial formation of O6-alkylguanine, which may be further enhanced by alkylation speci®c repair (Horsfall et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Determining mutational fingerprints at the human p53 locus with a yeast functional assay: a new tool for molecular epidemiology

Inga¹,

Iannone²,

Monti³

et al. 1997

Oncogene

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In order to isolate experimentally induced p53 mutations, a yeast expression vector harbouring a human wild-type p53 cDNA was treated in vitro with the antineoplastic drug chloroethyl-cyclohexyl-nitroso-urea (CCNU) and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. p53 mutations were identi®ed in 32 out of 39 plasmids rescued from independent ade-transformants. Ninety-two percent of CCNU induced mutations were GC-targeted single base pair substitutions, and GC4AT transitions represented 73% of all single base pair substitutions. In 70% of the cases the mutated G was preceded 5' by a purine. The distribution of the mutations along the p53 cDNA was not random: positions 734 and 785 appeared as CCNU mutational hotspots (n=3, P50.0003) and CCNU induced only GC4AT transitions at those positions. The features of these CCNU-induced mutations are consistent with the hypothesis that O6-alkylguanine is the major causative lesion. One third of the CCNUinduced mutants were absent from a huge collection of 4496 p53 mutations in human tumours and cell lines, thus demonstrating that CCNU has a mutational spectrum which is uniquely dierent from that of naturally selected mutations. This strategy allows direct comparison of observed natural mutation spectra with experimentally induced mutation spectra and opens the way to a more rigorous approach in the ®eld of molecular epidemiology.

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DNA base changes and alkylation following in vivo exposure of Escherichia coli to N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea.

Cited by 196 publications

References 40 publications

Frequency and Spectrum of Mutations at Codons 12 and 13 of the C-K-ras Gene in Human Tumors

Frequency and Spectrum of Mutations at Codons 12 and 13 of the C-K-ras Gene in Human Tumors

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Determining mutational fingerprints at the human p53 locus with a yeast functional assay: a new tool for molecular epidemiology

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