SEARCH · PubMed Health

Results for “Mutation spectrum”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2000

Toxicity, mutation frequency and mutation spectrum induced by dacarbazine in CHO cells expressing different levels of O(6)-methylguanine-DNA methyltransferase.

The toxicity and mutagenicity (including the mutation spectrum induced) of dacarbazine, a methylating cytostatic drug, was examined in CHO cells expressing different levels of the repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Expression of low or high levels of a transfected human MGMT gene under the control of the metallothionein promoter protected the cells against dacarbazine-induced toxicity and mutagenesis. In the absence of MGMT expression, the mutation spectrum in the HPRT locus was dominated by GC-->AT transitions (mostly found at 5'Pu-G sequences), while there were also a few AT-->GC transitions. Expression MGMT was associated with a substantial decrease of GC-->AT mutations, suggesting that these mutations arose primarily via O(6)-methylguanine. These data illustrate the important role of the latter lesion in the drug's mutagenic and cytotoxic activity.

Amino Acid Substitution↗

PubMed2004

Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia.

Propionic acidemia (PA) is an inborn error of organic acid metabolism caused by a deficiency of propionyl-CoA carboxylase. This enzyme is composed of two non-identical subunits, alpha and beta, which are encoded by the PCCA and PCCB genes, respectively. An enzyme deficiency can result from mutations in either PCCA or PCCB. To elucidate the mutation spectrum in Japanese patients, we have performed a mutation analysis of 30 patients with PA, which included nine previously reported patients. The study revealed that 15 patients were alpha-subunit deficient and 15 patients were beta-subunit deficient. Seven novel mutations were found (IVS18-6C >G, 1746G >A, C398R, G197E and IVS18+1G >A in the PCCA; A153P and IVS9+1G >T in the PCCB). Among these Japanese patients with alpha-subunit deficiencies, 923-924insT, IVS18-6C >G, and R399Q mutations were frequent and the total allelic frequency of these three mutations combined was 56% (17/30). This is in sharp contrast to the mutation spectrum found in Caucasian patients, where no prevalent mutations have been identified. Among the beta-subunit deficiencies, there were three frequent mutations; R410W, T428I, and A153P, whose allelic frequencies were 30, 26.7, and 13.3%, respectively. In conclusion, a limited number of mutations are predominant in both PCCA and PCCB genes among Japanese patients with propionic acidemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Low-energy (30 keV) carbon ion induced mutation spectrum in the LacZ alpha gene of M13 mp 18 double-stranded DNA.

Double-stranded M13 mp 18 DNA was irradiated with 30 ke V carbon ions in dry state under vacuum to investigate the low-energy heavy ion induced mutation spectra. When the irradiated DNA was used to transfect Escherichia coli JM 105, 3.6-5.7-fold increases in mutation frequency were observed, in contrast to the spontaneous group. Sequences of the 92 induced mutants showed that the carbon ions in this study could induce an interesting mutation spectrum in the lacZ alpha gene. One-base mutations (96.8%) and base pair substitutions (56.4%) were predominant, most of which involved G:C base pairs (90.6%), especially G:C --> T:A transversions (49.6%) and G:C --> A:T transitions (39.6%). This is similar to the spectra induced by gamma-rays in the same ds M13, wild type E. coli system. We also found a considerable amount of carbon ion induced one-base deletion (38.5%) and the mutation sites distribution on the target lacZ alpha gene was obviously non-random. We compared this study with previous data employing gamma-rays to discuss the possible causes of the mutation spectrum.

Base Sequence↗

PubMed1995

Mutational spectrum of X-ray induced TK- human cell mutants.

Mutations induced by ionizing radiation have historically elicited significant public concern. However, only a limited database of ionizing radiation-induced point mutations is available, particularly at endogenous human cell loci. Here, we report the mutational spectrum for 184 X-ray induced TK- mutants derived from TK6 human lymphoblasts. This report represents the first large scale utilization of the tk locus for investigation of mutational specificity at the DNA sequence level. Rapid, single nucleotide sequencing assays at frameshift polymorphism sites in tk exons 4 and 7 were used to partition TK- mutants into two groups: 126 were attributed to either partial gene deletion or to loss of heterozygosity, and DNA sequence alterations were identified for 51. X-ray-induced point mutations included all classes of transitions and transversions, tandem base substitutions, frameshifts, small deletions and a small duplication. The distribution within tk was characterized by clustering at some sites. Twelve TK- point mutations, including five entirely within the coding sequence in exons 3 and 4, resulted in aberrant splicing of the tk transcript. The spectrum of X-ray-induced point mutations was found to be highly reproducible when TK- mutations were compared with HPRT- mutations in TK6. A statistically significant decrease in transitions (P = 0.04) was observed in the combined data set as compared to the spontaneous background. These findings suggest a reproducible pattern which may be utilized in recognizing radiation-induced mutations at other loci of interest.

Alleles↗

PubMed2002

Differences in KRAS mutation spectrum in lung cancer cases between African Americans and Caucasians after occupational or environmental exposure to known carcinogens.

Elevated mortality rates of lung cancer in the Mississippi River corridor in Louisiana have been clearly documented for the past half-century and rank among the highest in the nation. A population-based case-control study of lung cancer termed Lower Mississippi River Interagency Cancer Study was conducted in southern Louisiana. Lung tumor specimens were collected, isolated by laser capture microdissection, subjected to PCR to amplify KRAS, and sequenced to confirm mutation status and specificity. Of the 116 lung tumors analyzed to date, 32 (27.6%) contained mutations in either codon 12 or 13 of KRAS. This frequency is comparable to that reported in the literature; however, the mutation spectrum was strikingly different. Of the 32 mutations observed, 21 (65.6%) resulted in the inappropriate insertion of cysteine, 6 (18.8%) resulted in the insertion of serine, 3 (9.4%) resulted in the insertion of valine, and 1 (3.1%) each resulted in the insertion of aspartate and alanine. These data indicate that an abnormally high proportion of cysteine (P = 0.010) and serine (P = 0.002) mutations was observed in our sample group versus lung cancers reported in the literature. KRAS mutations were more common in African Americans with an odds ratio of 2.4 (P = 0.048), as were serine mutations, although the latter did not reach statistical significance (odds ratio, 2.6; P = 0.373). No association was found between the observed mutation spectrum and known lung cancer risk factors.

Adult↗

PubMed1993

Mutagenicity and mutational spectrum of N-methyl-N'-nitro-N-nitrosoguanidine in the hprt gene in G1-S and late S phase of diploid human fibroblasts.

To investigate the effect of DNA replication on the mutation spectrum induced in diploid human fibroblasts by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), cells were synchronized and exposed to MNNG either at the G1-S border or in late S phase, and the mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene were examined. The coding regions of 92 independent mutants were characterized by direct sequencing of mRNA-polymerase chain reaction-amplified complementary DNA. While there was little difference in the sensitivity of the two populations to the cytotoxic effects of MNNG, the frequency of mutants induced in late S populations was significantly lower than that induced in G1-S populations. The majority of induced complementary DNA mutations were single base substitutions (54%) and splice site mutations (43%). Analysis of the intron-exon boundaries of more than one-half of the splicing mutants showed that almost all contained base substitutions in the hprt gene. A broad mutational spectrum was observed in low-dose (4, 6, or 8 microM) treatments; only 27% were G to A transitions, whereas 80% of base substitutions derived from the high-dose (10 or 12 microM) treatments were G to A transitions in G1-S populations. An intermediate frequency (64%) of G to A transitions was observed in late S populations exposed to MNNG. When the causative premutation lesion was O6-methylguanine, 75% of G to A transitions that were observed in G1-S populations clustered on both the transcribed and the nontranscribed strands of the 5' half of the hprt gene. In contrast, 50% of G to A transitions were located only on the nontranscribed strand of this region in late S populations. The results indicate that O(6)-alkylguanine-DNA-alkyltransferase may not efficiently remove O(6)-methylguanine from the 5' half of the gene but can repair lesions far away from this region during initiation of replication. Our results are consistent with the notion that the putative origin of replication is located at intron 1 of the hprt gene.

Amino Acid Sequence↗

PubMed2002

Mutational signature of the proximate bladder carcinogen N-hydroxy-4-acetylaminobiphenyl: inconsistency with the p53 mutational spectrum in bladder cancer.

We studied the mutagenicity of the proximate bladder carcinogen, N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) in embryonic fibroblasts of the Big Blue mouse. Treatment of these cells with increasing concentrations of N-OH-AABP for 24 h resulted in a dose-dependent increase in mutation frequency of the cII transgene up to 12.8-fold over the background. Single base substitutions comprised 86% of the N-OH-AABP-induced mutations and 74% of the spontaneous cII mutations (sequenced number of mutant plaques, 141 and 145, respectively). Of these, 63 and 36%, respectively, occurred at guanine residues along the cII gene. Whereas G to T transversions predominated in the induced cII mutations (47%), insertion was the most spontaneously derived cII mutation (19%). Mapping of N-OH-AABP-induced DNA adducts along the cII gene by terminal transferase-dependent PCR showed the formation of DNA adducts at specific nucleotide positions. Five preferential DNA adduction sites were established, of which four were major mutation sites for N-OH-AABP, especially for G to T transversions. This unique mutational signature of N-OH-AABP in the cII gene was, however, in sharp contrast with the mutational spectrum of the p53 gene in human bladder cancer. G to A transitions are the dominant type of p53 mutations (53%), being also prevalent in almost all of its five mutational hotspots (codons 175, 248, 273, 280, and 285). In addition, the majority of mutations in three of these hotspots (codons 175, 248, and 273) are at a methylated CpG site, whereas in the cII gene neither the preferential N-OH-AABP DNA adduction sites nor the induced mutational hotspots are biased toward methylated CpG dinucleotides. We conclude that N-OH-AABP leaves a characteristic mutational signature in the cII transgene, which is consistent with its preferential DNA adduction profile. However, the pattern of mutation induced by N-OH-AABP in the cII gene is largely at odds with the mutational spectrum of the p53 gene in human bladder cancer.

Aminobiphenyl Compounds↗

PubMed2001

Mutational spectrum of 1,3-butadiene and metabolites 1,2-epoxybutene and 1,2,3,4-diepoxybutane to assess mutagenic mechanisms.

1,3-Butadiene (BD) is a multisite carcinogen and is mutagenic in multiple tissues of B6C3F1 mice. BD is bioactivated to at least three directly mutagenic metabolites: 1,2-epoxybutene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB). However, the contribution of these individual metabolites to the carcinogenicity and in vivo mutatidnal spectrum of BD is uncertain. To assess the role of two BD metabolites EB and DEB in the in vivo mutagenicity of the parent compound BD, we examined the in vitro mutational spectra of EB and DEB in human and rodent cells. We also examined the in vivo mutagenicity and mutational spectrum of inhaled EB in the lung. In the bone marrow and spleen of B6C3F1 laci transgenic mice, BD-induced an increased frequency of the identical class of point mutations at A:T base pairs: AT-->GC transitions and AT-->TA transversions. BD exposure also induced an increased frequency of GC-->AT transitions in the spleen that was not observed in bone marrow, demonstrating tissue-specific differences in mutation spectrum. Exposure of Rat2 laci transgenic cells and human TK6 lymphoblasts to EB-induced an increased frequency of AT-->TA transversions. DEB exposure induced an increased frequency of AT-->TA transversions and partial deletions at hprt in human cells. In Rat laci transgenic cells, DEB was not mutagenic at laci but induced an increased frequency of micronuclei. In contrast to inhaled BD, inhaled DEB and EB were not mutagenic in the bone marrow or spleen. However, EB was mutagenic in the lungs. In the lung of mice, EB-induced specific increases in GC-->AT transitions, AT-->TA transversions, and deletion events. AT-->TA transversions are the most consistent mutation observed across biological systems following in vivo exposure to BD or in vitro exposures to EB and DEB. Although, BD exposure in mice induces chromosomal alterations and single base substitutions, the specific BD metabolite that induces the genetic events leading to tumors is uncertain. At present, it appears that only DEB can effectively induce this range of mutagenic events at levels of this metabolite that occur in the blood of mice exposed to BD. Detailed investigations to identify relevant biomarkers of BD exposure and response, particularly DNA adducts or lesions, that can be biologically linked to the range of genotoxic events known to occur in mice exposed to BD are needed.

Air Pollutants↗

PubMed2005

Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens.

BACKGROUND: Clinically affected cystic fibrosis (CF) patients present a spectrum of genital phenotypes ranging from normal fertility to moderately impaired spermatogenesis and congenital bilateral absence of vas deferens (CBAVD). Little is known about the CF incidence in the Taiwanese population. It has been shown that the CBAVD in men without clinical evidence of CF is associated with a high incidence of mutated CFTR (cystic fibrosis transmembrane conductance regulator) alleles. In order to understand the involvement of the CFTR gene in the aetiology of Asian/Taiwanese male infertility, we screened the entirety of the CFTR gene in 36 infertile males with CBAVD. METHODS: Temporal temperature gradient gel electrophoresis (TTGE) followed by direct DNA sequencing was used. RESULTS: Five mutations, p.V201M, p.N287K, c.-8G > C (125G > C), p.M469I and p.S895N, were found in five of the patients. p.N287K occurred in the first transmembrane-spanning domain, p.M469I in the first ATP-binding domain and p.S895N in the second transmembrane-spanning domain, were novel. In addition, seven homozygous and seven heterozygous 5T alleles in the intron 8 poly(T) tract were found. The overall frequency of CFTR mutant alleles in Taiwanese CBAVD males was 26 out of 72 = 36%. This finding was lower than the published frequency of CFTR mutations in other ethnic CBAVD patients (ranging from 50 to 74%). The frequency of p.M470V in Taiwanese CBAVD patients is not significantly different from that in the general population (P = 0.12). CONCLUSIONS: The results of this study add to the short list of Taiwanese/Asian CFTR mutations. Unlike Caucasian patients, the CFTR mutations cannot account for the majority of Taiwanese CBAVD. This is consistent with the low incidence of CF in the Asian/Taiwanese population. Furthermore, the mutation spectrum of CFTR in CBAVD patients does not overlap with the Caucasian CFTR mutation spectrum.

Asian People↗

PubMed2005

Mutation spectrum of type I glycogen storage disease in Hungary.

We performed mutation analysis in 12 Hungarian type I glycogen storage disease (GSD I) patients in order to determine the mutation spectrum. All patients were clinically classified as GSD Ia. Nine patients carried biallelic G6PC mutations (p.Q27fsX35, p.D38V, p.W70X, p.K76N, p.W77R, p.R83C, p.E110Q, p.G222R), with E110Q reported only in Hungary. However, three patients displayed two common G6PT1 (SLC37A4) mutations (p.L348fsX400, p.C183R) which were originally described in association with GSD Inon-a. Review of the literature and our data show that G6PT1 mutations are not associated with neutropenia and related clinical findings in approximately 10% of these cases. Homozygosity for the truncating G6PT1 mutation p.L348fsX400 can be observed with and without neutropenia, indicating that one or more modifiers of the action of G6PT1 exist. Our data are suitable to provide DNA-based and thus noninvasive confirmation of diagnosis in Hungarian patients with this disorder.

Age of Onset↗

PubMedDate not supplied

[The mutation spectrum of the CFTR gene in mucoviscidosis patients from Bashkortostan].

Mutations of CFTR were studied in patients with cystic fibrosis (CF) from Bashkortostan. In total, 15 mutations were observed and 51% of all mutant alleles identified. The most diagnostically significant mutations were delF508 (33.8%), 394delTT (3.52%), CFTRdele2.3(21 kb) (1.41%), R334W (1.41%), 3849+ 10 kbC-->T (1.41%), and N1303K (1.41%). Mutations G542X, 2184insA, S1196X, and W1282X were each found in less than 1% patients. Five new mutations and two neutral substitutions were revealed. These were I488M (exon 10), 1811 + 12A-->C (intron 11), T663S (exon 13), I1226R (exon 19), 4005 + 9A-->C (intron 20), 2097A-->C (A655A, exon 13), and 3996G-->C (V1288V, exon 20). Bashkortostan was shown to differ in CFTR mutation spectrum from other regions of Russia. The results will allow direct DNA diagnostics of CF in far more families. Molecular screening of probands' relatives will contribute to identification and medical genetic counseling of heterozygous carriers, which is essential for CF prevention.

Bashkiria↗

PubMed1985

Mutagenic effect and mutation spectrum induced by 3H decay in the 8th position of DNA purine bases in Saccharomyces cerevisiae.

Lethal and mutagenic effects and the mutation spectrum induced by 3H decay in the 8th position of adenine and guanine in yeast DNA have been studied. For haploid cells labelled with [8-3H]deoxyadenosinemonophosphate (8-3H-A) and [8-3H]deoxyguanosinemonophosphate (8-3H-G), the lethal efficiencies were determined as (3.0 +/- 0.8) X 10(-3) decay-1 and (3.8 +/- 0.6) X 10(-3) decay-1, respectively, and the mutagenic efficiencies as (5.7 +/- 1.1) X 10(-8) decay-1 and (8.7 +/- 1.4) X 10(-8) decay-1, respectively. The lethal effect of [8-3H]purines may be explained as being due to internal beta-irradiation. In contrast, the local effect of 3H-transmutation was twice as mutagenic as beta-irradiation when the induction of forward gene mutations was examined. Within the spectrum of mutations induced by 8-3H-G, a preference for GC----AT transitions was observed.

Genetic Complementation Test↗

PubMed2000

Subchronic administration of phenobarbital alters the mutation spectrum of lacI in the livers of Big Blue transgenic mice.

Phenobarbital (PHE) is a liver carcinogen in B6C3F1 mice and a weak mutagen that does not appear to form DNA adducts. To investigate PHE mutagenicity in vivo, B6C3F1 Big Blue(R) male transgenic mice harboring the lambdaLIZ shuttle vector containing the lacI target gene were fed PHE at 2500 ppm for 180 days. A modest increase in the mutant frequency (MF) from 5.02+/-2.4x10(-5) in the control group to 6.88+/-0.754x10(-5) in the PHE-treated group, which was marginally different (p<0.05), was obtained. To better assess the relevance of this increase in MF, a random collection of mutants from each PHE-exposed mouse was sequenced. After correcting for clonal expansion, which is the most conservative approach, the MF in the PHE-treated mice decreased to 6.39+/-1.02x10(-5), an insignificant difference (p=0.10) from that in control group. Despite this modest increase in MF, the mutation spectrum obtained from the PHE-exposed group was significantly different (pA:T transitions remained the same in the two spectra. It is postulated that the increase in transversions at G:C base pairs found in the PHE-derived spectrum is likely due to oxidative damage as a result of induction of CYP2B isozymes by the chronic administration of PHE. Results from this study demonstrate that PHE alters the spectrum of mutations, rather than inducing a significant global increase in the MF. The PHE-derived spectrum of lacI mutants from the liver of Big Blue(R) B6C3F1 male mice was remarkably similar (p=0.8) to that generated by oxazepam (OX), a compound which also induces CYP2B isozymes following chronic administration of the drug.

Animals↗

PubMed1998

The subclass approach for mutational spectrum analysis: application of the SEM algorithm.

Analysis and comparison of mutational spectra represents an important problem in molecular biology. To analyse a mutational spectra we apply an algorithm based on the SEM subclass approach (Simulation, Expectation, Maximization). The algorithm tries to classify the mutational sites according to different mutation probabilities, and each site should belong to one class. Each class is approximated by binomial distribution and thus any real mutational spectrum is regarded as a mixture of binomial distributions. The separation process runs iteratively. Each iteration includes the simulation, maximization and estimation procedures. To evaluate the quality of the classification results, the X2 test is used. The algorithm has been checked on random spectra with preset parameters and on real mutational spectra. As has been shown, 17 out of 19 analysed real mutational spectra can be divided into two or more classes of sites, of which one contains hotspots of mutation. For the G:C-->A:T mutational spectra induced by Sn1 alkylating mutagenes (11 spectra) the classification accuracy was 0.95. To test different site volumes, each Sn1-induced spectrum was divided into the G-->A and C-->T spectra. The classification accuracy for these spectra was 0.96. From the analysis of classification errors it is possible to suggest that at least part of them cannot be ascribed to the faults of the algorithm but are caused by some special features of the mutagenesis itself. The results of the real data are in good relation with existing knowledge. The approach we present is an attempt to formalize the concept of a "mutational hotspot". The program implementing the SEM algorithm is available on the Web server (http:/(/)www.itba.mi.cnr.it/webmutation).

Algorithms↗

PubMed2004

Mutational-reporter transgenes rescued from mice lacking either Mgmt, or both Mgmt and Msh6 suggest that O6-alkylguanine-induced miscoding does not contribute to the spontaneous mutational spectrum.

O6-methylguanine methyltransferase, Mgmt, constitutes the first line of defense against O6-alkylguanine, which can result in G : C to A : T transitions upon DNA replication. Mgmt has been found in organisms as diverse as archaebacteria and mammals. This evolutionary conservation suggests that all organisms may be exposed to either endogenous or environmental alkylating agents. We thus hypothesized that tissues of Mgmt-/- mice would exhibit elevated mutant frequencies. Employing the Big Blue trade mark transgenic system, we evaluated lacI mutants rescued from liver and small intestinal DNA of young Mgmt-/- mice. Interestingly, while there was a small difference between Mgmt-/- mice and controls with respect to lacI mutant frequency, no differences attributable to Mgmt deficiency were apparent in the mutational spectra. Although mutations stemming from O6-guanine alkylations would be predicted to be cumulative, we found no evidence of an Mgmt-dependent alteration in mutation spectrum in DNA samples from 12 month-old mice. To optimize our ability to detect mutations resulting from O6-alkylguanine-induced G : T mismatches, mice with combined deficiencies of Mgmt and the DNA mismatch repair molecule, Msh6, were analysed. In spite of this strategy, we observed no significant differences between Mgmt-/- Msh6-/- and Msh6-/- mouse lacI mutations, except for a trend towards a greater percentage (of total transitions) of G : C to A : T changes in Mgmt-/-Msh6-/- livers. Therefore, despite the striking evolutionary conservation of Mgmt, deficiency of this gene did not significantly impact the spontaneous lacI mutational spectrum in vivo.

Age Factors↗

PubMedDate not supplied

Study of 4-NQO induced mutations at the HPRT locus in CHO cell lines. Possible influences of preferential DNA-repair on the mutational spectrum.

In the attempt to determine the possible influence of excision repair processes on 4-NQO mutational spectra in mammalian cells, 4-NQO-induced mutants at the hprt locus were isolated in excision repair proficient (AA8) and deficient (UV5) CHO cell lines. DNA sequencing data on these mutants revealed that DNA repair may indeed modulate the induced mutational spectrum. In particular, more splice mutations were found in the repair proficient than in the repair deficient cells. This can be interpreted by a difference in repairability of the two principal 4-NQO G-adducts or by the existence of a transcription-coupled DNA preferential repair process.

4-Nitroquinoline-1-oxide↗

PubMed2005

TP53 mutation spectrum in lung cancer is not different in women and men.

Whether women are more susceptible to lung cancer than men has been controversial. Several case-control studies suggested that women have greater risk of lung cancer compared with men at similar levels of cigarette smoking, whereas some large cohort studies failed to observe this association. Other studies indicated that lung cancer may have biological characteristics and mechanisms of carcinogenesis that are gender specific. Therefore, we hypothesized that women are more susceptible to the carcinogenic effects of tobacco smoke exposure, as evidenced by a higher frequency of G:C-to-T:A somatic mutations in tumors from women in comparison with men at similar levels of tobacco smoke exposure. To investigate our hypothesis, we examined the TP53 mutational spectrum in a case-only (102 women and 201 men) series study where complete smoking information was available. A similar frequency and type of somatic TP53 mutations were observed in women and men. In conclusion, our study indicates that the TP53 mutation spectrum is similar in women and men. Our results are consistent with a recent large cohort study and summary of previous cohort studies, suggesting that women likely have equivalent susceptibility to lung cancer as men.

Female↗

PubMed2000

Carcinogen dose-dependent variation in the transgene mutation spectrum in urethane-induced lung tumors in transgenic mice carrying the human prototype c-Ha-ras gene.

Urethane-induced lung tumors and their genetic changes were investigated in transgenic (Tg) mice carrying a human prototype c-Ha-ras gene (rasH2 mice). Male and female rasH2 mice and non-transgenic (non-Tg) littermates were injected intraperitoneally with 1000 mg/kg of urethane once or three times at 2-day intervals. Hyperplasias and adenomas of the lung were observed in all animals of each group from week 10, and carcinomas were observed in male and female rasH2 mice of the triple injection group from week 10 and female non-Tg mice of the single injection group at 15/20 weeks. The multiplicities of lung proliferative lesions including hyperplasias, adenomas and carcinomas, in treated rasH2 mice were significantly higher than those in treated non-Tg mice. CAG to CTG transversions were observed in the c-Ha-ras gene in these lung proliferative lesions of rasH2 mice of the single injection group at high incidence (male: 58.3%, female: 62.5%), but no mutations of the mouse c-Ki-ras gene were evident in either rasH2 or non-Tg mice. In the triple injection group, transgene mutations were detected at a relatively low incidence, and mouse c-Ki-ras gene mutations(CAA to CGA) were observed in both rasH2 and non-Tg mice. These results suggest that the variation of the lesions induced by different doses of urethane was not the cause of the variation of the mutation spectrum and mutations of both transgene and mouse c-K-ras gene are not principal genetic events in urethane-induced lung proliferative lesions in rasH2 mice.

Animals↗