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Results for “mutational profiling”

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PubMed2005

The initiation of colon cancer in a chronic inflammatory setting.

Chronic inflammation predisposes to cancer. We used an inflammation-induced human model of tumorigenesis to explore how populations of mutated cells expand and initiate the earliest stages of cancer. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with an increased risk of colorectal cancer mediated through a process of genomic instability. In order to characterize the process of clonal expansion, arbitrary primed (AR) and inter-simple sequence repeat (ISSR) PCR DNA fingerprint mutation profiles of single crypts were compared with the mutational profiles from clusters of crypts and whole biopsies within the same individual. To provide information at the earliest steps of neoplastic progression, we examined histologically negative crypts, as well as dysplastic crypts. Crypts from UC dysplasia/cancer show alterations in 10-20% of DNA fingerprint sites, regardless of (i) whether the crypts were dysplastic or non-dysplastic and (ii) whether the DNA came from one crypt or thousands of crypts. Of the mutational changes in single crypts, almost half are clonally expanded to adjacent crypts and/or to the thousands of crypts in a single biopsy. Using fluorescent in-situ hybridization to examine p53 alterations in individual crypt cells, we demonstrate that the mechanism of clonal expansion can occur through crypt fission. DNA alterations are initiated in colonic crypts and expand to adjacent crypts through crypt fission. Our data suggest that a continuous process of DNA mutations, clonal expansion through crypt fission and clonal succession initiates the development of inflammatory-associated colon cancer; this mutational process is moderated by crypt cell turn-over and cell death. This paradigm may apply to other inflammatory-induced cancers.

Biopsy↗

PubMed1998

Comparison of the types of mutations induced by 7,12-dimethylbenz[a]anthracene in the lacI and hprt genes of Big Blue rats.

An important question regarding the use of transgenic reporter genes to detect mutation in rodents is how the types of mutations recovered in transgenes compare with the types of mutations found in endogenous genes. In this study, we examined mutations induced by 7,12-dimethylbenz[a]anthracene in the lacI transgene and the endogenous hprt gene of lymphocytes from Big Blue rats and in the hprt gene of lymphocytes from nontransgenic Fischer 344 rats. The overall mutation profiles found in these genes were remarkably similar: the majority of mutations were base pair substitutions, with the most common mutation being A:T-->T:A transversion. Differences were found for the mutational profiles in the endogenous gene and transgene with respect to the location of the mutations and the orientation of basepair substitutions in the DNA strands. In most cases, these differences could be explained by the nature of the target genes. The results support the use of the lacI transgene for detecting in vivo mutation.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer.

BACKGROUND & AIMS: Germline mutations in four DNA mismatch repair genes are known to cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). The rapidly increasing information about these mutations needs to be collected and appropriately stored to facilitate further studies on the biological and clinical significance of the findings. METHODS: The International Collaborative Group on HNPCC has established a database of DNA mismatch repair gene mutations and polymorphisms. In this report, 126 predisposing mutations were analyzed. RESULTS: A majority of the mutations affected either the Mut L homologue (MLH) 1 (n = 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite evenly distributed, with some clustering in MSH2 exon 12 and MLH1 exon 16. Most MSH2 mutations consisted of frameshift (60%) or nonsense changes (23%), whereas MLH1 was mainly affected by frameshift (40%) or missense alterations (31%). Although most mutations were unique, a few common recurring mutations were identified. Of the families studied (n = 202), 82% met the Amsterdam criteria and 15% did not; the general mutation profile was similar in both groups. CONCLUSIONS: The construction of mutation profiles will facilitate the development of diagnostic strategies in HNPCC.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Molecular characterization of hprt mutations from Chinese hamster ovary cells treated with 1-, 3-, and 6-nitrosobenzo[a]pyrene.

1-, 3-, and 6-nitrobenzo[a]pyrene (nitro-BaP) are environmental contaminants that can be metabolized to genotoxic derivatives by either nitroreduction or ring-oxidation. In this study, we examined the types of mutations produced by the primary nitroreduced metabolites, 1-, 3-, and 6-nitroso-BaP (NO-BaP) in the hprt gene of Chinese hamster ovary cells. RNA from 6-thioguanine-resistant mutants was reverse-transcribed to cDNA and the hprt coding sequence was amplified and sequenced. The mutational patterns produced by the three compounds exhibited extensive similarities: 1) base pair substitutions accounted for 67% (28/42) of 1-NO-BaP, 51% (26/51) of 3-NO-BaP, and 50% (11/22) of 6-NO-BaP mutations; 19-36% of the mutations were exon deletions and 14-18% were frameshifts; 2) most (64-84%) of the simple base pair substitutions occurred at G:C, mainly G:C-->T:A and G:C-->C:G transversions; 3) 98% (46/47) of the simple base pair substitutions at G:C had the mutated dG on the non-transcribed strand and 81% (38/47) were located with the mutated dG flanked 3' by at least one purine; and 4) most simple base pair substitutions (48/62, 77%) occurred in exons 2, 3, and 8 of the hprt gene. Although there were no significant differences among the mutation profiles of the NO-BaPs, a significant difference did exist between the mutation pattern produced by 3-NO-BaP and the mutation pattern previously determined for the ring-oxidized product of 3-nitro-BaP metabolism, trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9, 10-tetrahydro-3-nitrobenzo[a]pyrene. This observation indicates that differences in the structures of closely related adducts can be important enough to have an effect on mutation profiles.

Animals↗

PubMed2026

Clinical and genetic features of Ph-negative myeloproliferative neoplasms with dual-driver gene positivity.

OBJECTIVES: To investigate the clinical laboratory characteristics and gene mutation features of dual-driver gene positivity in patients with Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-negative MPN). METHODS: We conducted a retrospective analysis of clinical data and genetic test results from 203 newly diagnosed patients with Ph-negative MPN. Of these, 194 had single-driver gene positivity and 9 had dual-driver gene positivity. High-throughput sequencing was used to detect mutations in JAK2, CALR, and MPL. Clinical characteristics and gene mutation profiles were compared between the two patient groups. RESULTS: The incidence of dual-driver gene positivity was 4.4% (9/203), with the most common combinations being JAK2 with CALR (4 patients) and JAK2 with MPL (4 patients). Compared with the single-driver group, the dual-driver group had a significantly higher risk of bleeding [4.1% (8/194) vs. 33.3% (3/9), P = 0.008] and a higher proportion of uncommon mutations [3.6% (7/194) vs. 33.3% (3/9), P = 0.006]. No statistically significant differences were observed between the two groups regarding age, thrombosis incidence, splenomegaly, or routine blood test indicators. During follow-up, 1 patient in the dual-driver group died from cerebrovascular disease. No leukaemia transformation or disease-related deaths occurred among the remaining patients. DISCUSSION: The increased bleeding risk in dual-driver patients may be related to a higher proportion of CALR mutations, elevated platelet counts, and higher variant allele frequencies, though these findings require validation in larger cohorts due to the small sample size. The higher prevalence of uncommon mutations suggests a more complex mutational landscape in this subgroup. CONCLUSION: Patients with Ph-negative MPN and dual-driver gene positivity may have a higher risk of bleeding and a more complex gene mutation profile.

Humans↗

PubMed2002

Prevalence and profile of mutations associated with lamivudine therapy in Indian patients with chronic hepatitis B in the surface and polymerase genes of hepatitis B virus.

Lamivudine results in the selection of resistant hepatitis B virus (HBV) variants. Because the surface gene of HBV overlaps completely the polymerase gene, the incidence and profile of surface and polymerase gene mutations were investigated prospectively in chronic HBV patients who were on lamivudine therapy. Twenty-six patients with chronic liver disease confirmed histologically were included in this study. Extracted HBV DNA from sera samples were subjected to PCR amplification for the mutation prone regions of the surface and polymerase genes of the HBV genome. The emergence of mutant forms and biochemical derangements were studied carefully during the course of the therapy. In six of 26 (23%) patients, mutations emerged on lamivudine therapy. YM552I/VDD resistant mutants were observed in one (6%) and five (29%) patients at Month 12 and 18, respectively, out of 17 patients, who had completed more than 9 months of therapy. The mean time of emergence of resistance was 16.4 +/- 6.8 months. In three of the five patients, emergence of YM552I/VDD mutation was accompanied with a rise in HBV DNA levels. In two patients, mutations were noticed at the end of the viral breakthrough; when the DNA level went down to undetectable levels (<0.5 pg/mL). In two patients, normal ALT levels were found at the time of emergence of the YMDD mutation. YM552I/VDD mutations were observed in 43% of HBeAg positive and 20% of anti-HBe positive patients (P = ns). Although the 'a'-determinant region was found to be unaffected; in one patient, a novel pattern due to emergence of YIDD mutant was observed; the corresponding aa in the S-ORF turned to a stop codon. In summary, the frequency of emergence of YM552I/VDD mutations was 29% at Month 18 in the Indian patients. The presence of normal ALT and low levels of HBV DNA do not exclude the existence of resistant mutants. Novel mutations in the S-ORF, which lead to premature surface gene termination might affect the production of HBsAg and need further study.

Anti-HIV Agents↗

PubMed1991

Activation of proto-oncogenes in human and mouse lung tumors.

Lung cancer is a leading cause of cancer-related deaths in several nations. Epidemiological studies have indicated that 85% of all lung cancer deaths and 30% of all cancer deaths in the U.S. are associated with tobacco smoking. Various chemicals in tobacco smoke are thought to react with DNA and to ultimately yield heritable mutations. In an effort to understand the molecular mechanisms involved in lung tumorigenesis, we have analyzed proto-oncogene activation in a series of human lung tumors from smokers and spontaneously occurring and chemically induced lung tumors in mice. Approximately 86% of the human lung tumors and greater than 90% of the mouse lung tumors were found to contain activated oncogenes. ras Oncogenes activated by point mutations were detected in many of the human lung adenocarcinomas and virtually all of the mouse lung adenomas and adenocarcinomas. The mutation profiles of the activated K-ras genes detected in the chemically induced mouse lung tumors suggest that the observed mutations result from genotoxic effects of the chemicals. Comparison of the K-ras mutations observed in the human lung adenocarcinomas with mutation profiles observed in the mouse lung tumors suggest that bulky hydrophobic DNA adducts may be responsible for the majority of the mutations observed in the activated human K-ras genes. Other data indicate that approximately 20% of human lung tumors contain potentially novel transforming genes that may also be targets for mutagens in cigarette smoke.

3T3 Cells↗

PubMed2005

CLL biology and prognosis.

Chronic lymphocytic leukemia (CLL) follows an extremely variable course with survival ranging from months to decades. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in CLL patients. In particular, the mutational profile of Ig genes and some cytogenetic abnormalities have been found to be important predictors of prognosis in CLL. However, this progress has raised new questions about the biology and prognosis of the disease, some of which are addressed here. Such questions include: 1) What is the role of the B-cell receptor (BCR) in CLL pathogenesis? 2) Is CLL one disease? 3) Is CLL an accumulative disease? 4) What is the normal counterpart of the CLL B lymphocyte? 5) Have the Rai and Binet staging systems become obsolete? 6) Which is the best surrogate for Ig mutational profiles?

DNA Mutational Analysis↗

PubMed1997

p53 mutations in squamous cell carcinoma of the head and neck predominate in a subgroup of former and present smokers with a low frequency of genetic instability.

We examined the p53 mutational profile of 65 squamous cell carcinomas of the head and neck (SCCHNs) from patients living in northwest England. Twenty-three p53 mutations were detected in 20 samples (31%). GC-->AT transitions were the predominant type of mutation. The p53 mutational profile of SCCHN tumors was similar to that of non-small cell lung tumors from patients within the same geographical area, supporting the idea of a common model for carcinogenesis in the upper respiratory tract. Statistical analysis showed that the incidence of p53 mutations among present and former smokers was significantly higher than that in nonsmokers (P < 0.02). In addition, p53 mutations were found to predominate in a group of SCCHN patients with low genetic damage, as indicated by the fractional allelic loss value. The above findings suggest an early initiating role for p53 and imply that at least two separate carcinogenic pathways may be involved in the development of SCCHN.

Alcohol Drinking↗

PubMed2002

Identification by RNA profiling and mutational analysis of the novel copper resistance determinants CrdA (HP1326), CrdB (HP1327), and CzcB (HP1328) in Helicobacter pylori.

Mechanisms involved in maintaining cytoplasmic metal ion homeostasis play a central role in the adaptation of Helicobacter pylori to the changing gastric environment. An investigation of the global regulatory responses to copper ions by using RNA profiling with a threshold factor of 4.0 revealed that copper induces transcription of 19 H. pylori genes and that only the ferritin gene pfr is repressed. The 57-fold copper induction identified the HP1326 gene encoding an H. pylori-specific protein as a candidate for a novel copper resistance determinant. The HP1326 gene is expressed as a monocistronic unit, and two small HP1326 mRNAs are copper induced. The HP1326 protein is secreted and is required for copper resistance maintained by cytoplasmic copper homeostasis, as H. pylori HP1326 mutants were copper sensitive and displayed increased copper induction of HP1326 transcription as well as elevated copper repression of ferritin synthesis. The clear copper-sensitive phenotype displayed by H. pylori HP1327 and HP1328 mutants provides strong evidence that the HP1326 protein, together with the signal peptide site of the H. pylori-specific protein HP1327, whose gene is located downstream from that encoding HP1326, and the CzcB and CzcA metal efflux system component homologs HP1328 and HP1329, constitutes a novel type of copper efflux pump, as discussed below. The HP1329 gene could not be inactivated, but the 14-fold transcriptional copper induction determined by RNA profiling points towards a function of the encoded CzcA homolog in copper resistance. In summary, results from RNA profiling identified the novel H. pylori-specific copper resistance determinants CrdA (HP1326) and CrdB (HP1327), which are required for adaptation to copper-rich environmental conditions.

Amino Acid Sequence↗

PubMed2006

Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.

PURPOSE: This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features. EXPERIMENTAL DESIGN: Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC). RESULTS: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor. CONCLUSION: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.

Adenocarcinoma↗

PubMed2001

Types and localisation of p53 gene mutations: a report on 332 non-small cell lung cancer patients.

Mutations of p53 suppressor gene are among the most common molecular abnormalities in human malignancies. We demonstrated earlier significant differences in mutational profiles between NSCLC patients from Poland and Spain. These differences were most probably related to ethnic and/or geographical factors. In the present study we analyzed the types and location of p53 gene mutations in a large group of 332 operated NSCLC patients from two institutions in Northern Poland. Within the last decades this region has been characterized by the highest incidence of lung cancer in Poland. We used both frozen and paraffin-embedded tumor samples and the screened region included exons from 5 to 8. A total of 96 samples (29%) were positive for p53 gene mutation. The proportion of mutations in particular exons was as follows: exon 5-33%, exon 6-22%, exon 7-16%, and exon 8-29%. Three 'hot spots' were located in codons 176,245 and 248. Evolutionary conserved domains were much more frequently affected than the regions outside domains. The majority of mutations (73%) were missense type, followed by null and silent mutations (21 and 6%, respectively). In all six silent mutations substituted was the third base in codon. There were no major differences in the types and locations of mutations between patients from the two institutions. This homogeneity, together with our earlier findings, may confirm the impact of ethnic and geographical factors on the mutational profile of p53 gene in NSCLC.

Aged↗

PubMed2005

Identification of EGFR kinase domain mutations among lung cancer patients in China: implication for targeted cancer therapy.

Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

Adenocarcinoma↗

PubMed1997

Alterations in the K-ras and p53 genes in rat lung tumors.

Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarcinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 to 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors.

Animals↗

PubMed2004

In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir.

Emergence of lamivudine-resistant hepatitis B virus (HBV) is a major concern in human immunodeficiency virus (HIV) and HBV coinfected patients. Following selection of resistant mutants, hepatitis flare or rapid progression to cirrhosis may occur. Treatment of patients with new nucleotide analogues such as adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF) has shown good efficacy in controlling wild-type or lamivudine-resistant HBV replication. The purpose of this study was to assess the in vitro efficacy of new nucleotide analogues on HBV strains isolated from lamivudine-treated patients. After purification of HBV DNA from patient sera, the whole HBV genome was PCR-amplified and cloned. Drug sensitivity was measured after transfection of the isolated full genomes into HepG2 cells and measurement of HBeAg, HBsAg and viral replication in the culture media under increasing drug concentrations. A wild-type strain isolated from an untreated patient served as control. In a clinical study of ADV (Gilead 460i study), seven of the 35 patients carried HBV strains with the triple lamivudine resistance-associated amino-acid changes rtV173L/L180M/M204V at baseline. Although all patients responded to ADV in this clinical study, the serum HBV reduction was lower in the seven patients with the triple mutation (median -3.3 log copies/ml) compared to the patients who had only the rtL180M/M204V mutations (median -4.1 log copies/ml) at week 48 (P=0.04, Mann-Whitney test). In our in vitro system, lamivudine IC50 on lamivudine-resistant HBV carrying amino-acid substitutions rtL180M and rtM204V within the polymerase encoding region increased by more than 16,000-fold (from 6 nM to over 100 microM) when compared to wild-type HBV. For ADV and TDF, comparison of wild-type and lamivudine-resistant HBV IC50 (rtL180M-M204V) showed, respectively, 2.85-fold (from 0.07 to 0.2 microM) and 3.3-fold (from 0.06 to 0.2 microM) increases, indicating a mild decrease of both drug activities, in vitro. At the ADV concentration of 0.1 microM, presence of the V173L mutation reduced the inhibition of HBsAg production from 50 to 30% (P<0.01) and the viral replication from 45 to 32% (P<0.01, Mann-Whitney). Conversely, tenofovir had similar potency on both HBV mutation profiles with 60% inhibition of HBsAg production and 45% inhibition of viral replication at 0.1 microM. Our study supports the high efficacy of ADV and TDF seen in patients after lamivudine breakthrough. The excellent activity of TDF on lamivudine-resistant virus independently of the resistance mutation profile offers an interesting treatment alternative to HIV-HBV coinfected patients.

Adenine↗

PubMed2004

Mutation analysis of hMSH2 and hMLH1 in colorectal cancer patients in India.

The aim of this work was to study the mutation profile in hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients in India. On the basis of the Bethesda criteria, 31 colorectal cancer patients were studied first for microsatellite instability, using the five markers recommended by the Bethesda guidelines. Twelve of 31 tumor samples were found to be MSI-H, 9 of 31 were MSI-L, and the rest were MSS. The 12 patients with MSI-H were analyzed for mutations in hMSH2 and hMLH1 genes using PCR-denaturing high-performance liquid chromatography (dHPLC), followed by sequencing of samples showing abnormal peaks. Of the five mutations detected, three were found to be deleterious mutations (hMSH2-R680X, hMLH1-E671X, and a splice junction mutation IVS16-2A --> G); one had a mutation of probable significance (hMLH1-C680G) and one was of unknown significance (hMSH2-R171K). This study has also shown that most of the early-onset colon (4/7) and early-onset rectal (15/21) cancers are MSS or MSI-L. This is the first study to describe the mutation in hMSH2 and hMLH1 in Indian patients, a low incidence region for colorectal cancer. A two-stage procedure using MSI testing followed by PCR-dHPLC was found to be an efficient method in studying the mutation profile in high-risk patients.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Specificity of base substitution mutations induced by the dietary carcinogens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Salmonella.

The base pair substitution mutational profiles induced by the heterocyclic amine cooked food mutagens PhlP and IQ in Salmonella typhimurium strains TA100 and TA1535 were determined by colony hybridization analysis. Both PhlP and IQ induced predominantly GC-->TA transversions in strain TA100 (rfa,delta uvrB/pKM101) with a pronounced preference for the second codon position (CCC--> CAC; 72% of total). PhlP also reverted strain TA1535 (rfa, delta uvrB) efficiently at concentrations similar to those required for strain TA100. In contrast to the PhlP-induced mutational profile observed in strain TA100, in strain TA1535 PhlP induced exclusively GC-->AT transitions at the second codon position (CCC-->CTC; 96-99% of total). Base substitution mutagenesis induced by heterocyclic amines related to PhlP is generally SOS-dependent, requiring the presence of plasmid pKM101 in Salmonella hisG46 strains. Thus, the SOS dependent reversion of S. typhimurium strain TA100 probably reflects error-prone lesion bypass at the major PhlP- guanosine adduct at the C-8 position. The GC-->AT transition mutations induced by PhlP in strain TA1535 appear to be SOS-independent, however, suggesting that these mutations may arise from the formation of PhlP-DNA adducts other than the replication-blocking C8-dG lesion.

Carcinogens↗

PubMed2005

Pseudogene accumulation might promote the adaptive microevolution of Yersinia pestis.

Plague is a natural focus-based disease, and for better understanding of this disease it is crucial to determine the molecular mechanisms of its pathogen, Yersinia pestis, for adapting to different foci. Gene inactivation, loss and acquisition are the main mechanisms that contribute to a pathogen's fitness. Determination of the whole-genome sequences of three Y. pestis strains, CO92, KIM and 91001, provided a good opportunity to probe into its genome in minute detail. Many genetic variations were found between the three strains. The present work focused on adaptive microevolutionary analysis of Y. pestis from different natural plague foci in China based on pseudogene profiles. Twenty-four mutations that led to inactivation in the corresponding genes were analysed, and a PCR-based screening method was employed to investigate the distribution of these mutations among Y. pestis isolates from different foci and also among seven strains of Yersinia pseudotuberculosis. It was found that Y. pestis isolates from the same focus had identical mutation profiles, and 260 isolates of Y. pestis were divided into eight genotypes, while Y. pseudotuberculosis harboured wild-type alleles for all the mutations. The isolates of three known biovars were grouped into distinct branches in the phylogenetic tree, which supports the proposition that biovars mediaevalis and orientalis directly arose from biovar antiqua individually. The constructed phylogenetic tree suggests that the isolates from focus B should be the oldest lineage of Y. pestis in China except for isolates from foci L and M, which might be a special lineage of Y. pestis and originated differently to the others.

Adaptation, Physiological↗