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PubMed2006

Genetic population structure of the soil bacterium Myxococcus xanthus at the centimeter scale.

Myxococcus xanthus is a gram-negative soil bacterium best known for its remarkable life history of social swarming, social predation, and multicellular fruiting body formation. Very little is known about genetic diversity within this species or how social strategies might vary among neighboring strains at small spatial scales. To investigate the small-scale population structure of M. xanthus, 78 clones were isolated from a patch of soil (16 by 16 cm) in Tübingen, Germany. Among these isolates, 21 genotypes could be distinguished from a concatemer of three gene fragments: csgA (developmental C signal), fibA (extracellular matrix-associated zinc metalloprotease), and pilA (the pilin subunit of type IV pili). Accumulation curves showed that most of the diversity present at this scale was sampled. The pilA gene contains both conserved and highly variable regions, and two frequency-distribution tests provide evidence for balancing selection on this gene. The functional domains in the csgA gene were found to be conserved. Three instances of lateral gene transfer could be inferred from a comparison of individual gene phylogenies, but no evidence was found for linkage equilibrium, supporting the view that M. xanthus evolution is largely clonal. This study shows that M. xanthus is surrounded by a variety of distinct conspecifics in its natural soil habitat at a spatial scale at which encounters among genotypes are likely.

Bacterial Proteins↗
PubMed1998

B-cell monoclonality precedes the development of gastric MALT lymphoma in Helicobacter pylori-associated chronic gastritis.

Little is known about the temporal changes in Helicobacter pylori density and B-cell clonality during the evolution from chronic gastritis to gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Biopsied specimens from 28 patients with chronic gastritis who developed gastric MALT lymphoma (group A) and from 24 similar patients who did not (group B) during an equivalent follow-up period (mean, 42 months) were retrospectively scored for histological features of MALT lymphoma (0 to 5) and H. pylori density (0 to 3). B-cell clonality was analyzed by polymerase chain reaction (PCR). During the observation period, the H. pylori density in group A decreased significantly in comparison with group B; the mean change in H. pylori density (final minus initial density) per 1000 days was -1.4 for group A and +0.2 for group B (P < 0.005). Monoclonality was detected more frequently in group A (79%) than in group B (21%; P < 0.005), and it preceded the histological evidence of malignant transformation in 64% of those patients who showed monoclonality in group A. These results suggest that H. pylori is thus more closely associated with the precursor or initial phase in the genesis of gastric MALT lymphoma than with the later phase, as its density decreases as the tumor progresses. The detection of B-cell monoclonality by PCR is thus of possible use for predicting the histological genesis of gastric lymphoma.

Adolescent↗
PubMed1999

Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor.

It is important to understand how low grade tumors recur and progress to malignant lesions since this dramatically shortens patient survival. Here, we evaluated the concept that malignant progression and poor prognosis of low grade astrocytic tumors are TP53 dependent through clonal expansion of mutated cells. TP53 status was established in primary and recurrent tumors from 36 patients with WHO grade II astrocytic tumors and two tumor types were found. Tumors from 14 patients (39%; type 1) had TP53 mutated cells, and 92% of these recurred with 57% progressing to malignancy. The evolution of TP53 mutated cells before and after progression was examined using a clonal analysis procedure in yeast. Malignant progression was accompanied by an increased percentage of mutant TP53 (red) yeast colonies resulting from monoclonal expansion of cells with mutated TP53. The presence of TP53 mutations in WHO grade II astrocytic tumors was associated with malignant progression (P=0. 034, chi2 test) and shorter progression-free survival (PFS; 47.6+/-9. 6 months for TP53-mutated tumors vs 67.8+/-8.2 months for TP53-wild type tumors, P<0.05, log-rank test). Tumors from 22 patients (61%; type 2) were without TP53 mutations, and 64% of these recurred without a change in TP53 status, although 41% progressed to malignancy. This suggests that TP53 mutation is not an initiating or progression event in the majority of low grade astrocytic tumors. Our study also indicates that irradiation for WHO grade II astrocytic tumors might be associated with poor outcome (P<0.0001) and this was independent of TP53 status. These findings have important implications in the clinical management of patients with low grade astocytoma and provide new support to the clonal evolution model for tumor progression.

Adolescent↗
PubMed1987

Clonality of angioimmunoblastic lymphadenopathy and implications for its evolution to malignant lymphoma.

To investigate the relationship of the lymphoid hyperplasia of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) to supervening malignant lymphoma, we subjected DNA from lymph nodes and peripheral blood mononuclear cells from five AILD patients to Southern blot analysis to detect clonal rearrangements of immunoglobulin and T-cell receptor genes. Lymph nodes and peripheral blood from AILD patients were found to contain clones of lymphoid cells harboring either immunoglobulin or T-cell receptor gene rearrangements that, in some instances, regressed during the course of disease. A lymph node from one patient was involved by immunoblastic lymphoma and manifested an additional gene rearrangement pattern not seen in premalignant specimens from that patient. In contrast, DNA obtained from normal peripheral blood mononuclear cells and 11 examples of other forms of lymphoid hyperplasia showed no gene rearrangements. As a disorder of cellular immunoregulation in which lymphoid cells may escape normal growth controls, AILD provides a natural model to dissect stages of lymphomagenesis in man.

Cells, Cultured↗
PubMed2003

Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family.

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique to W-Beijing phylogenetic lineage. Analysis of the mut genes in 55 representative W-Beijing isolates suggests a sequential acquisition of the mutations, elucidating a plausible pathway of the molecular evolution of this clonal family. The acquisition of mut genes may explain in part the ability of the isolates of W-Beijing type to rapidly adapt to their environment.

Amino Acid Sequence↗
PubMed2003

Impact of large chromosomal inversions on the adaptation and evolution of Pseudomonas aeruginosa chronically colonizing cystic fibrosis lungs.

Pseudomonas aeruginosa chronically colonizing the lungs of cystic fibrosis (CF) patients undergoes fast evolution leading to clonal divergence. More than half of the genotypes of P. aeruginosa clone C isolates exclusively from CF lung infection exhibit large chromosomal inversions (LCIs). To analyse the impact of LCIs, as a novel mechanism of bacterial adaptation, the underlying molecular mechanism was examined. Analysis of inversion breakpoints suggested an IS6100-induced coupled insertion-inversion mechanism. A selective advantage was created by insertion of IS6100 into wbpM, pilB and mutS which leads to common CF phenotypes such as O-antigen and type IV pili deficiency and hypermutability. Speciation in bacteria is accompanied by LCIs. Therefore adaptation by LCIs that allows persistence of P. aeruginosa in the CF lung and species diversification in that new ecological niche can serve as a model for bacterial genome evolution.

Adaptation, Physiological↗
PubMed2001

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course.

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)

Adult↗
PubMed2003

Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors.

Tumor progression to metastasis usually is assumed to occur through clonal genomic and epigenetic evolution. However, present evidence that challenges this paradigm. They show that genomic aberrations in tumor cells disseminated in the bone marrows of patients with no clinical evidence of metastasis generally do not resemble the aberrations in the primary tumors from which they arose. They interpret this to mean that tumor cells disseminate very early and evolve to metastatic disease independent from the primary tumor. Their model suggests that adjuvant therapies should be targeted to lesions in the disseminated cells rather than lesions found in primary tumors.

Animals↗
PubMed1994

Clonality and karyotype studies in polycythemia vera.

The molecular determination of the monoclonal or non-clonal nature of polycythemia cases is now possible in all or almost all females by study of the methylation pattern of several polymorphic X-linked loci. However, the techniques used are sophisticated and costly and the results do not clarify all cases. Karyotypic studies of PV, despite the number of cases reported thus far, remain insufficient. The natural history of cytogenetic events and their mechanisms of occurrence are still poorly known. Unsuccessful examinations are around 10-15%. The proportion of patients with clonal anomalies, 10-15% at diagnosis, increases with time, myelo-ablative treatments and evolution to myelofibrosis/myeloid metaplasia, so as to be close to 100% in cases with myelodysplasia/acute transformation. A few of the most frequently found non-random anomalies among which in particular trisomy 8 and 9, double trisomy 8+9, 20q- and trisomy of part or totality of 1q have some degree of specificity. Other recurring aberrations, such as 13q- mainly occur in late stages of PV, in which complex, unstable karyotypes are found. Finally none of those anomalies can be considered as a primary lesion. The frequency of clonal evolution is a matter of discussion. Despite their theoretical interest, PV cytogenetic results are of little diagnostic value, and as regards prognosis, they are statistically significant, but are of poor value in most individual patients. In conclusion, it is felt that clonality and karyotype studies should be pursued in PV, completed by "interphase cytogenetics" and molecular biology investigations, with theoretical aims rather than for immediate practical reasons.

Cloning, Molecular↗
PubMed2004

Clonal variation of the immunogenotype in relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia indicates subclone formation during early stages of leukemia development.

Recent data suggest that late relapses evolve from an ancestral ETV6/RUNX1-positive (also designated TEL/AML1-positive) clone resulting from secondary changes (ETV6 deletion) that differ from those of the initial leukemia and, as a consequence, may also deviate in their clonotypic immunoglobulin/T-cell receptor (IG/TCR) gene rearrangements. The aim of our study was to compare the immunogenotype and fluorescence in situ hybridization (FISH) patterns of the unrearranged ETV6 allele of matched diagnosis/relapse samples from 12 children with an early or late relapse. We identified varying degrees of differences in the IG/TCR in six of them. A clonal change or evolution of the unrearranged ETV6 allele was also observed in six children but remained unchanged in three. However, these two parameters were not in concordance, nor did the immunogenotype pattern correlate with the duration of the first remission. We therefore propose that the potential of the immunogenotype to diversify depends primarily on the stage of IG/TCR gene configuration of the cell in which the ETV6/RUNX1 gene fusion takes place.

Child↗
PubMed1996

Study of clonality in myelodysplastic syndromes: detection of trisomy 8 in bone marrow cell smears by fluorescence in situ hybridization.

The lineage involvement in myelodysplastic syndromes (MDS) is still unclear. To determine the clonality and the evolution of the disorder, a retrospective study on bone marrow smears from seven MDS patients with trisomy 8 was performed using fluorescence in situ hybridization (FISH). We observed that the trisomy of chromosome 8 was selectively expressed in the myeloid-derived cells. No mature lymphocytes or plasma cells expressed three signals. Our studies demonstrate here the value of FISH for identifying the affected cell lineage. Furthermore, the easy quantification of the abnormal cells can help in assessing the progression of the disease.

Aged↗
PubMedDate not supplied

Transcriptional analyses of Barrett's metaplasia and normal upper GI mucosae.

Over the last two decades, the incidence of esophageal adenocarcinoma (EA) has increased dramatically in the US and Western Europe. It has been shown that EAs evolve from premalignant Barrett's esophagus (BE) tissue by a process of clonal expansion and evolution. However, the molecular phenotype of the premalignant metaplasia, and its relationship to those of the normal upper gastrointestinal (GI) mucosae, including gastric, duodenal, and squamous epithelium of the esophagus, has not been systematically characterized. Therefore, we used oligonucleotide-based microarrays to characterize gene expression profiles in each of these tissues. The similarity of BE to each of the normal tissues was compared using a series of computational approaches. Our analyses included esophageal squamous epithelium, which is present at the same anatomic site and exposed to similar conditions as Barrett's epithelium, duodenum that shares morphologic similarity to Barrett's epithelium, and adjacent gastric epithelium. There was a clear distinction among the expression profiles of gastric, duodenal, and squamous epithelium whereas the BE profiles showed considerable overlap with normal tissues. Furthermore, we identified clusters of genes that are specific to each of the tissues, to the Barrett's metaplastic epithelia, and a cluster of genes that was distinct between squamous and non-squamous epithelia.

Barrett Esophagus↗
PubMed1982

Evolution of tumor cell heterogeneity during progressive growth of individual lung metastases.

The metastatic properties of tumor cell clones isolated from individual lesions of B16 melanoma metastatic to lung have been examined at different stages in the evolution of metastasis. Clonal analysis of metastatic lesions produced by B16 melanoma populations containing clones with identifiable, stable drug-resistance markers revealed that the majority (greater than 80%) of experimental metastases produced by intravenous injection of tumor cells are of unicellular origin. During the early stages of their growth (less than 25 days after initial tumor cell arrest), the majority of metastatic lesions contain cells with indistinguishable metastatic phenotypes (intralesional clonal homogeneity) although different clonally homogeneous lesions from the same host contain tumor cells with different metastatic phenotypes (interlesional clonal heterogeneity). Progressive growth of metastatic lesions is accompanied by emergence, within originally clonally homogeneous lesions, of variant tumor cells with altered metastatic properties (intralesional clonal heterogeneity). By 40-45 days after initial arrest of injected tumor cells in the lung, 90% of the metastatic lesions are populated by cells with heterogeneous metastatic phenotypes.

Animals↗
PubMed2003

Emergence and spread of gentamicin-susceptible strains of methicillin-resistant Staphylococcus aureus in Belgian hospitals.

The aim of this study was to follow the evolution of the clonal distribution and antimicrobial susceptibility of clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) recovered from Belgian hospitals between 1995 and 1997-1998. MRSA strains were genotyped by inter-IS256 spacer length polymorphism PCR and SmaI macrorestriction analysis. MICs of 18 antimicrobials were determined by the agar dilution method. MRSA strains from the 1997-1998 survey were further tested by vancomycin screen agar, E-test, broth microdilution methods, and population analysis. Between 1995 and 1997-1998, epidemic group A strains decreased in proportion from 73% to 44%, whereas MRSA Group B and C strains increased from 17% to 38% and from 5% to 8%. The proportion of strains susceptible to gentamicin increased between the surveys from 22% to 48%. This was associated with a higher proportion of group B and C strains in the last survey. Heterogeneous vancomycin-intermediate S. aureus (hetero-VISA) strains were found in 2% isolates from 1997 to 1998. These hetero-VISA isolates were genotypically related to the MRSA group A strains and were resistant to gentamicin. In conclusion, two emerging epidemic MRSA genotypes, susceptible to gentamicin, have spread among Belgian hospitals during the 1990s. Hetero-VISA were present at low frequency among MRSA strains belonging to a widespread endemic genotype.

Aged↗
PubMed1994

A Rational Appraisal of Bone Marrow Transplantation and Immunosuppressive Therapy for Severe Aplastic Anemia.

With significant improvements in the rates of graft rejection and acute graft-vs-host disease, bone marrow transplantation remains the therapy of choice for the young aplastic anemia patient with an HLA-matched related donor. While immunosuppressive therapy can induce responses in a significant proportion of patients, long-term follow-up studies have demonstrated a high rate of relapses and evolution to malignant clonal hematopoietic disorders. Therefore, this therapeutic option should be considered for patients who are not transplant candidates. The potential roles for hematopoietic growth factors and alternative marrow donors needs to be further defined.

Journal Article↗
PubMedDate not supplied

Breast cancer heterogeneity assessed by flow cytometry.

The natural history of breast cancer is characterized by a marked heterogeneity within and between patients. During the clinical phase, there is ample opportunity for clonal mutation and evolution, and it seems probable that almost all breast cancer patients have multiple tumor clones, each with its own growth requirements, growth rate, ability to metastasize and sensitivity to drugs. Flow cytometry (FCM) is a technique which can rapidly and quantitatively measure a wide variety of cellular features. This can explain its large employment in the development and validation of tumor markers for prognostic and therapeutic purposes. The study of DNA content and cell cycle represents the most common application of FCM on solid tumor analysis. The use of monoclonal antibodies raised against functional and phenotypic cell markers can improve the suitability of FCM to assess the prognostic significance of these parameters; at the same time it could provide a helpful tool for a combined investigation of differentiation, proliferation and aggressiveness tumor markers, and their clinical relevance.

Breast Neoplasms↗
PubMed1997

A neuroblastoma cell line derived from a case detected through a mass screening system in Japan: a case report including the biologic and phenotypic characteristics of the cell line.

BACKGROUND: A mass screening system in Japan, which involves measuring urinary catecholamine metabolites, has resulted in an increasing number of cases of neuroblastoma, most of which have favorable biologic properties and some of which are associated with tumor regression or involution. At the time this study was begun, the characteristics and biologic nature of the neuroblastomas had not been fully defined, because a cell line had not yet been established with tumor tissue taken from a neuroblastoma detected in the mass screening. METHODS: The authors established a cell line by tissue culture for over 50 generations from a neuroblastoma found during mass screening, which was characterized by favorable histology, with a triploid DNA stemline and without N-myc gene amplification. The morphologic and biologic characteristics of the new cell line were investigated in vitro. RESULTS: The cell line, designated MASS-NB-SCH-1, has neuronal properties, such as neurite-like processes and neurofilaments, as well as the expression of vimentin and fibronectin in studies of the cell morphology and immunohistochemistry. Karyotype analysis detected the presence of 42-46 chromosomes, with a deletion of the short arm of 1 of the 3 copies of chromosome 1. DNA ploidy was near-diploid in association with 20-fold amplification of N-myc genes. CONCLUSIONS: The cell line has a nature distinct from the original tumor tissue. It may be characterized by phenotypic change caused by clonal selection or evolution of aggressive, proliferative properties in vitro. This cell line will be a useful model to investigate the properties of the neuroblastoma in relation to the N-myc amplification mechanism.

Biology↗
PubMed2004

[Clinical significance of continuous karyotyping in myelodysplastic syndromes].

OBJECTIVE: To explore the relationship between evolution of karyotype and clinical progress in myelodysplastic syndromes (MDS) and estimate the clinical outcomes of high risk patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Continuous karyotyping were performed using short-term culture of bone marrow cells and G-banding technique to follow up 41 cases of MDS patients. RESULTS: Karyotype analysis showed that 24 cases (58.5%) had clonal karyotypic abnormalities. In a median follow up of 34 months (7 approximately 72 months), 6 cases had karyotype evolution in 12 cases with clinical deterioration, while only one had karyotype evolution in 18 cases without clinical progression. The involved chromosomes included No. 2, 4, 7, 8, 10, 11, 17 and 21. Six out of 7 patients who received allo-HSCT attained complete remission and their abnormal karyotypes returned to normal. Four patients with clinical remission after therapy attained cytogenetic remission too. CONCLUSION: Karyotype evolution showed a strong relationship with clinical progress in MDS patients, and indicated a very poor prognosis. Patients with clinical progress had much higher incidence of clonal evolution than those with relatively stable clinical course. Allo-HSCT should be considered the first choice of therapy for MDS patients with clonal karyotypic abnormalities.

Adolescent↗