SEARCH · PubMed Health

Results for “mutational profiling”

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 145 records · Page 8Linked to original sources

PubMed2005

Spectrum of beta-globin gene mutations among thalassemia patients in the West Bank region of Palestine.

beta-Thalassemia (thal) is an autosomal recessive disorder that results in hypochromic hemolytic anemia in affected patients. In the West Bank area of Palestine, the prevalence of beta-thal trait is approximately 3.5% among the population, with an estimated 120,000 carriers. Seventeen beta-globin gene mutations could be identified in 148 patients using polymerase chain reaction (PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing. The predominant mutations included: IVS-I-6 (T --> C) (28.7%), IVS-I-110 (G --> A) (17.6%), codon 37 (G --> A) (10.4%), IVS-I-1 (G --> A) (9%), codons 106/107 (+ G) (6.8%) and codon 39 (C --> T) (4.6%). Other less frequent and rare mutations included: IVS-II-1 (G --> A), codon 5 (-CT), IVS-II-848 (C --> A), -30 (T --> A), codons 8/9 (+ G), IVS-I-5 (G --> C), -28 (A --> C), IVS-II-745 (C --> G), codon 6(-A), codon 27 (G --> T) and codon 30 (AGG --> ACG). Most patients (62.2%) were homozygous for one type of mutation, while the rest (27.3%) were compound heterozygotes. Some patients were heterozygous for beta-thal and sickle cell anemia traits. No mutations could be detected in both alleles of eight patients, while in seven patients only one mutant allele could be detected. Further investigations are needed to resolve the corresponding genotypes of these patients. This study represents a comprehensive investigation of the type, frequency, and distribution of thalassemia mutations among the Palestinian population in the West Bank region of Palestine. A degree of similarity and significant variations was evident in the type and frequency of mutations when the present mutations profile was compared with similar ones among various Arab and non Arab populations. The association between the identified mutations and the corresponding genotypes of our patients with specific polymorphism frameworks in the beta-globin gene was performed and the results revealed linkage disequilibrium.

Adolescent↗

PubMed1995

A model for the evolution of the genome: the effect of stochasticity on genetic loads.

In this paper a general model is given for the evolution of the genome incorporating stochastic factors. The model is applied to the substitutional genetic load problem. All of the major hard selection load formulae in the literature are extended and, where necessary, corrected (for stochasticity). Turning to rank selection, formulae for stochastic factors are also corrected and harmful mutations included. A simple formula for the selection coefficient as a function of the nonneutral substitution rate and the mutation profile is obtained. Further, it is noted that the formulae derived also apply (for different parameter values) to the mutation load, thus unifying the two loads under a single theory. A general formula for the mutation load under hard selection is given, extending previous results. Finally, the author derives a formula showing how many harmful mutations can be effectively eliminated by rank selection and discusses its relevance to the question of the possible buildup of harmful mutations in the human gene pool due to long-term exposure to low-level radiation.

Animals↗

PubMed2003

Mechanisms of esophageal cancer development in Brazilians.

Esophageal cancer represents one of the most common and lethal cancers around the World. Some areas of South America, including parts of Brazil, present the highest incidence of the disease in the West. The main etiological factors that have been associated with the disease in Brazil are alcohol consumption, tobacco smoking and, in the South, consumption of hot maté. Nitrosamines are the only carcinogens capable of inducing tumors in the esophagus of experimental animals, with the rat being the most susceptible species, mainly due to tissue specific metabolic activation by CYP enzymes. Studies of CYP2A expression in the esophagus of rodents suggest an association between CYP2A expression and esophageal susceptibility to tumor induction. CYP2A6 and CYP2E1, the main enzymes to activate nitrosamines in humans, are the only carcinogen activating CYP enzymes to be expressed in the esophagus of Brazilians. Patients who presented high levels of CYP2A6 expression could activate nitrosamines at rates comparable to the rat. This expression profile is different from those present in French patients. We investigated 34 Brazilian patients regarding the risk associated with polymorphisms in drug metabolizing enzymes and TP53 mutations. A GSTP1 polymorphism presented a clear risk to white and non-white patients to develop esophageal cancer. GSTM1 null polymorphism also seemed to be associated with an increased risk. CYP2A6, CYP2E1, SOD2, and GSTT1 polymorphisms were not associated with an increased risk of esophageal cancer. TP53 mutations occurred mostly in exon 7, differing from the mutation profile found in the IARC database. The preliminary results obtained with polymorphisms of drug metabolizing enzymes and TP53 mutations need to be confirmed in a larger number of samples in order to compare the mechanisms of esophageal cancer development in Brazilians with that of other populations.

Alcohol Drinking↗

PubMed2025

Construction and accuracy assessment of an efferocytosis-related prognostic model for ovarian cancer: A diagnostic accuracy study.

The study aimed to investigate the prognostic significance of efferocytosis-related genes in ovarian cancer (OC) with regard to cancer development, progression, invasion, and metastasis. OC cohorts were assembled from bioinformatics repositories. Utilizing consensus clustering analysis, distinct clusters were delineated based on the intersection of OC-related genes and efferocytosis-related genes. A prognostic signature specific to efferocytosis in OC was developed using data from The Cancer Genome Atlas, validated against the gene expression omnibus database, and subjected to independent prognostic analysis. Subsequently, a nomogram model was formulated. Moreover, investigations encompassed the immune microenvironment, immunotherapy, mutation profiling, drug sensitivity assessments, drug prediction models, and molecular docking analyses. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were employed to ascertain the mRNA expression levels of key genes. Five key genes, FCGBP, BTN3A3, WDR91, SLC25A45, and BTNL3, were identified as significantly associated with OC. Both datasets and qRT-PCR demonstrated elevated expression levels of FCGBP and WDR91 in OC. Notably, AFLATOXIN B1 exhibited strong binding affinity to SLC25A45, ciclopirox to BTN3A3, and irinotecan to WDR91. The risk score, age, and stage were identified as independent prognostic factors, with the nomogram displaying efficacy in predicting OC patient survival. Variations in the immune cell infiltration profiles, including naive B cells, and expression levels of 6 immune checkpoint genes, such as CTLA4, were notable. High tumor mutation burden scores were associated with improved survival outcomes. Additionally, significant differences in the IC50 values of 123 anticancer drugs were observed between the 2 risk groups. This findings of this study highlight the efficacy of the efferocytosis-associated risk model in predicting the survival outcomes of OC patients, thus providing a novel reference for prognostic prediction in OC patients.

Humans↗

PubMed2026

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

PubMed1999

Mutations in ras genes in experimental tumours of rodents.

Studies of carcinogenesis in rodents are valuable for examining mutagenesis in vivo. An advantage of evaluating the frequency and spectra of ras mutations in chemically induced neoplasms is that the additional data at the molecular level indicate whether the carcinogenic effect is due to the chemical and is not a spontaneous event, as illustrated by the numerous examples in Appendices 1 and 2. In addition, data on the frequency and spectra of ras mutations in spontaneous and chemically induced neoplasms clearly expand the toxicological database by providing information helpful for understanding the pathogenesis of carcinogenesis. For example: (1) ozone-induced lung neoplasms had two unique mutations, one (codon 61 K-ras CTA mutation) consistent with a direct genotoxic event and a second (codon 12 K-ras G --> T transversion) consistent with an indirect genotoxic effect; (2) isoprene-induced Harderian gland neoplasms had a unique K-ras A --> T transversion at codon 61 which provided evidence that formation of an epoxide intermediate was involved; (3) 1,3-butadiene-induced neoplasms had a characteristic K-ras G --> C transversion mutation at codon 13 which was also consistent with a chemical-specific effect; (4) methylene chloride-induced liver neoplasms had an H-ras mutation profile at codon 61 similar to that of spontaneous tumours, suggesting that methylene chloride promotes cells with 'spontaneously initiated' ras mutations and (5) oxazepam-induced liver neoplasms had a low frequency of ras mutations, suggesting a nonmutagenic pathway of carcinogenesis. By extending the evaluation of rodent tumours to include molecular studies on ras mutation spectra and abnormalities in other cancer genes with human homologues, a number of hypotheses can be tested, allowing the most complete understanding of carcinogenesis in rodents and in potential extrapolation to the human risk situation.

Animals↗

PubMed2003

Mutations induced by (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of dibenzo[a,l]pyrene in the coding region of the hypoxanthine phosphoribosyltransferase (Hprt) gene in Chinese hamster V79 cells.

The polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) is an exceptionally potent carcinogen. Its direct DNA-reactive metabolite, the fjord region (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide [(-)-anti-DB[a,l]PDE], was used to investigate induction of mutations in the coding region of the hypoxanthine phosphoribosyltransferase (Hprt) gene in Chinese hamster V79 cells. Cells exposed to 1-10 nM (-)-anti-DB[a,l]PDE exhibited a close dose-responsive increase in the frequency of mutant clones resistant to 6-thioguanine. RNA was isolated from mutant clones and cDNAs were prepared by reverse transcription. The coding region of the cDNA of the Hprt gene was amplified by polymerase chain reaction and sequenced. Analysis of the DNA base sequence changes induced by (-)-anti-DB[a,l]PDE indicated that base substitutions were the most prevalent mutations, followed by exon deletions. Among the groups of V79 cells treated with low concentrations of (-)-anti-DB[a,l]PDE, most displayed high selectivity for both A:T-->T:A transversions and A:T-->G:C transitions, while cells exposed to a higher dose (10 nM) formed predominantly G:C-->T:A transversions. Also, the number of base substitutions per mutant clone increased with dose. In general, the mutation profiles induced by (-)-anti-DB[a,l]PDE exhibited a wide spectrum; in addition to base substitutions, deletions, insertions, frameshift mutations, as well as tandem mutations were detected. Analysis of the DNA adduct levels induced by (-)-anti-DB[a,l]PDE revealed that a concentration-dependent increase in the level of adduct formation preceded the concentration-dependent increase in mutational events in these cells and that an increasing proportion of DNA adducts at deoxyadenosine were formed with dose. The results of this study demonstrate a correspondence between the concentration and types of DNA adducts and the frequency and types of mutations induced by (-)-anti-DB[a,l]PDE in V79 cells.

Animals↗

PubMed1997

How are model protein structures distributed in sequence space?

The figure-to-structure maps for all uniquely folding sequences of short hydrophobic polar (HP) model proteins on a square lattice is analyzed to investigate aspects considered relevant to evolution. By ranking structures by their frequencies, few very frequent and many rare structures are found. The distribution can be empirically described by a generalized Zipf's law. All structures are relatively compact, yet the most compact ones are rare. Most sequences falling to the same structure belong to "neutral nets." These graphs in sequence space are connected by point mutations and centered around prototype sequences, which tolerate the largest number (up to 55%) of neutral mutations. Profiles have been derived from these homologous sequences. Frequent structures conserve hydrophobic cores only while rare ones are sensitive to surface mutations as well. Shape space covering, i.e., the ability to transform any structure into most others with few point mutations, is very unlikely. It is concluded that many characteristic features of the sequence-to-structure map of real proteins, such as the dominance of few folds, can be explained by the simple HP model. In analogy to protein families, nets are dense and well separated in sequence space. Potential implications in better understanding the evolution of proteins and applications to improving database searches are discussed.

Amino Acid Sequence↗

PubMed2025

SISTEM: simulation of tumor evolution, metastasis, and DNA-seq data under genotype-driven selection.

SUMMARY: SISTEM is a software package and mathematical framework for simulating tumor evolution and cell migrations at single-cell resolution. Unlike existing frameworks which simulate cancer cell populations under the neutral coalescent or using simple birth-death models, SISTEM simulates tumor populations under somatic clonal selection using an agent-based framework. SISTEM can generate mutation profiles, read counts, and DNA sequencing reads along with ground truth cell lineages and migration graphs under a number of easily customizable mutation and selection models. For improved realism, SISTEM allows for cell fitness to be driven by genomic events of various scales including single nucleotide variants, segmental gains and losses, whole-chromosomal and chromosome-arm aberrations, and whole-genome duplications. SISTEM also includes numerous migration models to simulate metastatic cancers, facilitating the exploration and evaluation of diverse migration patterns. AVAILABILITY AND IMPLEMENTATION: SISTEM is written in Python and is freely available open-source under GNU GPLv3 from: https://github.com/samsonweiner/sistem.

Software↗

PubMed2006

Directed evolution by accumulating tailored mutations: thermostabilization of lactate oxidase with less trade-off with catalytic activity.

We assumed that adverse effects posed by introducing multiple mutations could be decomposed into those of each of the component mutations and that the risk could be reduced by the accumulation of mutations that were finely tuned for directed improvement of a specific property. We propose here a directed evolution strategy for improving a specific property with less effect on other ones. This strategy is composed of fine-tuning of mutations and their accumulation by our original mutation-assembling method. In this study, we selected lactate oxidase (LOX) as a model enzyme, because its directed evolution had showed a trade-off between thermostability and catalytic activity. Mutation profiling at each of the sites found by error-prone PCR revealed a strong inverse relationship between the two properties. Thermostable mutations with less effect on catalytic activity were selected at each site and accumulated with ideal combinations by our method. The resultant multiple mutants exhibited 5- to 10-fold superior catalytic activity and comparable thermostability with those created by accumulating thermostable mutations, which were not tuned for catalytic activity. This result demonstrates that the accumulation of fine-tuned mutations is an advantageous approach to reduce the risk of adverse effects posed by accumulating multiple mutations.

Amino Acid Substitution↗

PubMed2026

Establishment of Stable Immortalized Human Choroidal Melanocytes for Ocular Research.

PURPOSE: The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. METHODS: NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. RESULTS: NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. CONCLUSIONS: NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.

Humans↗

PubMed2025

Genomic and Transcriptomic Landscape of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Multicenter Study.

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-infected mesenchymal cell that differentiates along the follicular or fibroblastic dendritic cell pathway. Despite its rarity, it presents a pressing need for an improved understanding of its genetic underpinnings and potential treatment strategies for recurrent or disseminated cases. To address this, we conducted comprehensive whole-exome sequencing and transcriptome sequencing (mRNA-seq) analyses on 31 and 6 cases of EBV+ IFDCS, respectively, collected from multiple centers in China. We also compared the genetic features of EBV+ IFDCS with those of other EBV-associated malignancies. Our analyses revealed a relatively high somatic mutation rate and widespread copy number variations affecting the major histocompatibility complex-I/II in EBV+ IFDCS. Integrated mutational profiling identified key signaling pathways involved in epigenetic regulation, NF-κB signaling, RTK/RAS/PI(3)K, and the Hippo pathway. Furthermore, we identified several frequently altered genes that could serve as potential therapeutic targets in EBV+ IFDCS. Transcriptomic analysis unveiled significant upregulation of pathways related to virus infection, immune responses, and multiple immune checkpoint genes in EBV+ IFDCS. Comparative analysis demonstrated clear genetic distinctions between EBV+ IFDCS and other EBV-associated tumors. In conclusion, our study provides comprehensive insights into the unique genomic and transcriptomic landscape of EBV+ IFDCS. We have identified multiple genetic alterations that likely contribute to the development and progression of this malignancy. Our results suggest that targeted therapy and immune checkpoint inhibitors may hold promise as potential therapeutic approaches for patients with recurrent or disseminated EBV+ IFDCS.

Humans↗

PubMed2006

Defining clinically relevant molecular subsets of lung cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, induce dramatic responses in certain patients with non-small cell lung cancer (NSCLC). As such, the drugs provide an unexpected tool to dissect clinically relevant molecular subsets of NSCLC. For example, using mutational profiling of tumor DNA from patients with sensitivity, primary resistance, and secondary resistance to these agents, we and others have demonstrated that somatic mutations in the tyrosine kinase domain of EGFR are associated with sensitivity to gefitinib and erlotinib, while mutations in KRAS, which encodes a GTPase downstream of EGFR, are associated with primary resistance. Furthermore, second site mutations in the EGFR kinase domain are commonly found in patients with acquired resistance. We are now using a variety of molecular and biological approaches to help further define molecular subsets of lung cancer that have relevance in the clinic.

Drug Resistance, Neoplasm↗

PubMed2000

[Prevention of renal carcinoma: the nutri-genetic approach].

The development of renal cell carcinoma (RCC) has been associated with both genetic and environmental factors, with somatic and germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and with tobacco smoking, obesity, long term exposure to some nutrients, pollutants, and industrial solvents such as trichloroethylene. Intra and interfamilial variability of expression of germline mutations in the VHL gene and variable susceptibility to carcinogens in the sporadic forms strongly suggest the involvement of conditional modifier genes. In order to identify sub groups of individuals at increased risk because of susceptibility genotypes, we have collected a series of 460 patients who developed an RCC and 79 families with the von Hippel Lindau disease. To collect clinical and mutational data for correlation analysis we have developed a unique tool the Universal Mutation Database. Comparison of the spectrum of germline and somatic mutations in the VHL gene showed that: 1) in sporadic RCC mutations lead more often to truncated proteins (83%), while the remaining mutations (17%), include 3/4 of transversions and 1/4 of transitions. This high proportion of transversions supports the involvement of carcinogens the impact of which is conditioned by the genetic variability of xenobiotic metabolizing enzymes; 2) whereas in familial cases missense mutations are more common; this difference allowed us to define a prognostic factor for the occurrence of RCC in a VHL context. In order to look for genotypes conferring a higher risk we genotyped the RCC patients for 8 different genes (50 genotypes). A significant relationship was observed for several combinations of alleles including CYP1A1 ("variant"), NAT2 and NAT1 (slow) and GSTM1 (null allele). Associations between specific mutational profiles and at risk genotypes at different tumoral stages should allow us to: 1) define more precisely the nature of specific patterns of mutations in relation with the deficiency or overexpression of such or such enzymes in presence of particular carcinogens; 2) demonstrate that certain combinations of genotypes confer a particular risk to develop a specific type of tumor in VHL patients. Thus tracking of potentially carcinogenic substances, through their footprints and through identification of conditionally detrimental genotypes of genes participating in their detoxification should permit a better prevention through an appropriate nutrition adapted to each individual.

Acetylation↗

PubMed1995

Characterization of hprt splicing mutations induced by the ultimate carcinogenic metabolite of benzo[a]pyrene in Chinese hamster V-79 cells.

The molecular basis for putative aberrant splicing of hypoxanthine (guanine) phosphoribosyltransferase (hprt) pre-mRNA in Chinese hamster V-79 cells was determined for 75 independent (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene [(+)-BPDE]-induced and 6 spontaneous 8-azaguanine-resistant mutant clones that had exon deletions in their hprt cDNA. Genomic DNA fragments corresponding to the missing exons and their flanking intron regions were amplified by PCR and sequenced. The results indicated that each of these mutants generated a normal-sized PCR product and resulted from aberrant splicing. For (+)-BPDE-induced aberrant splicing mutants, 81% (61 of 75 clones) had base substitution mutations, 5% (4 of 75 clones) had a single base deletion, and 13% (10 of 75 clones) lacked a detectable mutation in the skipped exon, its flanking intron sequences, or in the upstream donor site of the preceding intron. All mutations at a splice donor site resulted in skipping of the entire upstream neighboring exon, whereas alterations at a splice acceptor site caused skipping of the downstream neighboring exon or activation of a cryptic acceptor site in the downstream exon. Fifty-nine % of the splicing mutants had a mutation occurring at the splice site consensus sequence in the intron, and 28% of the splicing mutants had mutations within exon sequences. Among 21 aberrant splicing mutant clones with a mutation inside an exon sequence, seven were in exon 2, two were in exon 3, and twelve were in exon 4. Evidence is presented that a stemloop structure sequesters the splice donor site of exon 2 in pre-mRNA and plays a role in exon 2 skipping. Mutant clones with mutations stabilizing the proposed stemloop structure inhibited the use of the normal exon 2 splice site which resulted in exon 2 skipping in the hprt mRNA. These mutant clones expressed a mixed population of mRNAs, and both normal-sized and truncated mRNA were formed. Similar to our earlier finding that treatment of V-79 cells with (+)-BPDE resulted in a dose-dependent mutation profile within the coding region of the hprt gene, we also observed the presence of dose-dependence in the profile of (+)-BPDE-induced base substitutions in aberrant splicing mutants. As the dose of (+)-BPDE was decreased, the proportion of base substitution mutations at AT base pairs that affected RNA splicing was increased.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2005

What do somatic hypermutation and class switch recombination teach us about chronic lymphocytic leukaemia pathogenesis?

B-CLL cells express CD5 and IgM/IgD and thus have a mantle zone-like phenotype of naive cells, which, in normal conditions express unmutated Ig genes. However, recent studies have shown that 50%-70% of CLL harbour somatic mutations of VH genes, as if they had matured in a lymphoid follicle. Interestingly, the presence or absence of somatic hypermutation (SHM) process is associated with the use of particular VH genes. Particular alleles of the VH1-69 gene and the VH4-39 gene are preferentially expressed in an unmutated form, while VH4-34 or the majority of VH3 family genes frequently contain somatic mutations. The fact that some genes like VH1-69 and VH3-07 recombine this VH segment to particular JH segments and the restricted use of CDR3 sequences by CLLs expressing the VH4-39 gene suggest that the observed differences in BCR structure in B-CLL could result from selection by distinct antigenic epitopes. It is currently unclear whether this putative antigen-driven process could occur prior to leukaemic transformation and/or that the precursors were transformed into leukaemic cells at distinct maturational stages. The mutational profile of Ig genes has been shown to be associated with disease prognosis. These results could favour the idea that CLL could correspond to two different diseases that look alike in morphologic and phenotypic terms. In CLL with mutated Ig genes, the proliferating B cell may have transited through germinal centres, the physiologic site of hypermutation, whereas in CLL with unmutated Ig genes the malignant B cell may derive from a pre-germinal centre naïve B cell. Despite these clinical and molecular differences, recent studies on gene expression profiling of B-CLL cells showed that CLL is characterized by a common gene expression signature that is irrespective of Ig mutational status and differs from other lymphoid cancers and normal lymphoid subpopulations, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Activation induced cytidine deaminase (AID) plays a key role in SHM and class switch recombination (CSR). However, the mechanisms accounting for AID action and control of its expression remain unclear. In a recent work we have shown that in contrast to normal circulating B-cells, AID transcripts are expressed constitutively in CLL patients undergoing active CSR, but interestingly this expression occurs predominately in unmutated CLL B-cells. These data favour the view that AID protein may act differentially on CSR and SHM pathways, but the role-played by AID in both processes remains to be elucidated. Recent work indicates that AID is expressed in a small fraction of tumoral cells, which could suggest that this small fraction of cells may correspond to B-CLL cells that would have recently experienced an AID-inducing stimulus occurring in a specific microenvironment.

B-Lymphocytes↗

PubMed1995

p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure.

Angiosarcomas of the liver are rare, malignant cancers composed of neoplastic blood vessels. Human hapatic angiosarcomas have been associated with liver cirrhosis or exposure to vinyl chloride, Thorotrast or arsenic. A recent analysis of six hepatic angiosarcomas associated with vinal chloride exposure found three mutations and all were A:T --> T:A transversions, which are otherwise uncommon in human cancers. To test the specificity of this mutation spectrum, we analyzed 21 hepatic angiosarcomas not associated with vinyl chloride exposure. Four cases were exposed to Thorotrast, none had a history of arsenic exposure and the rest were sporadic. Exons 5-8 of the p53 gene were amplified by polymerase chain reaction, and the products were sequenced directly. Two G:C --> A:T transitions were found in two tumors: TGCstop in codon 136. Neither mutation was associated with Thorotrast exposure. These data indicate that p53 mutations are uncommon in sporadic hepatic angiosarcomas (2/21, 9%), and the mutational profile is consistent with endogenous mechanisms. Both features support the evidence linking vinyl chloride exposure to hepatic angiosarcomas containing an increased frequency of p53 mutations with a mutational spectrum (i.e. A:T --> T:A transversions) characteristic of chloroethylene oxide, a carcinogenic metabolite of vinyl chloride.

Adult↗

PubMed1999

Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population.

Albinism is a heterogeneous group of genetic disorders resulting from deficiencies in pigmentation. Clinically, it is divided into ocular (OA) and oculocutaneous albinism (OCA). OCA involves lack of pigment in the skin, hair, and eyes and results from mutations in the tyrosinase gene or in the P gene. OA mainly affects pigmentation in the visual system and may be a mild form of OCA or may be caused by other genetic defects. Clinical diagnosis of albinism type is difficult, because of the observed range of phenotypic variation. Thus, genetic analysis may be helpful with respect to a more accurate diagnosis. Here, we report the mutational profile, determined by genetic analysis of the tyrosinase and P genes, of a large German albino population. We have revealed a total of 42 distinct mutations, 19 of which are novel. Of the 74 unrelated patients screened, 32 (43%) had mutations in the tyrosinase gene, 16 (22%) had P gene mutations, and 26 (35%) patients had no detectable genetic abnormalities. This defines a population of albino patients who are tyrosinase-gene- and P-gene-negative and who thus may represent a good study group for searching for additional genes associated with albinism.

Albinism, Oculocutaneous↗