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At least 1,153 records · Page 64Linked to original sources
PubMed2003

BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma.

Follicular lymphoma (FL) is characterized by a relatively indolent clinical course, but the disease often transforms into a more aggressive large cell lymphoma with a rapidly progressive clinical course. In the present study, we analyzed 41 cases of FL known to have subsequently transformed to aggressive lymphoma and an additional 64 FL samples from patients not subsequently transformed. We studied BCL6 gene rearrangement by the methodology of long-distance inverse polymerase chain reaction (LDI-PCR). Of the 41 cases known to transform, 16 (39.0%) harbored BCL6 translocation or deletion at the time of FL diagnosis. Among 64 cases not known to transform, BCL6 translocation was detected in 9 (14.1%). The prevalence of BCL6 translocation in the group known to transform was significantly higher (P =.0048). Among the transformation cases, the partners of the BCL6 translocation were identified in 13 cases and included IGH, CIITA, U50HG, MBNL, GRHPR, LRMP, EIF4A2, RhoH/TTF, and LOC92656 (similar to NAPA), whereas in the control group the BCL6 partners were IGH, CIITA, SIAT1, and MBNL. In 13 cases paired specimens before and after transformation were available. Among these paired specimens, a loss (3 cases) or a gain (1 case) of BCL6 translocation was observed after the transformation. Analysis of clonality showed that all of these cases represented the evolution of a subclone of the original tumor population. Our study demonstrated that BCL6 translocation is not necessary for transformation but that BCL6 translocation in FL may constitute a subgroup with a higher risk to transform into aggressive lymphoma.

Cell Transformation, Neoplastic↗
PubMed1991

Mutation of the p53 gene in human acute myelogenous leukemia.

Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.

Base Sequence↗
PubMed1990

Clonotypic heterogeneity in cutaneous T-cell lymphomas.

The antigen receptor genes studied (immunoglobulin gene for B-cells, and T-cell receptor -beta or -gamma gene for T-cells) represent the most powerful tools for diagnosing the clonality of a lymphoid lineage. We have clonotyped 23 cutaneous T-cell lymphomas and 5 were found to be clonotypically all heterogeneous. Analysis of each patient was performed either from serial skin biopsies taken several months apart or from different tumor samples. In these cases, T-cell lymphoma clonotypic heterogeneity was demonstrated and was especially evident when examining different tumor sites. Moreover, in one case, a biogenotypic population (immunoglobulin and T-cell receptor-rearranged) was found. This unexpected high frequency of T-cell clonal heterogeneity (22%) could be explained either by the evolution of subclones from a single undifferentiated malignant cell or by the independent transformation to cancer of 2 or more lymphocytes, though the latter seems less likely. Clonotypic heterogeneity seems to be as frequent in T-cell lymphomas with cutaneous lesions as in B-cell leukemias.

Gene Rearrangement↗
PubMed1996

Faconi anemia and bone marrow clonal chromosome abnormalities.

Clonal chromosome abnormalities were detected in bone marrow cells of 20 patients with Fanconi anemia investigated at various stages of the disease. Two presented with acute leukemia, six with myelodysplastic syndrome, and 12 had minor or no morphological abnormalities of hematopoietic cells. Abnormalities of chromosome 7 were detected in nine patients (monosomy, isochromosome, or other structural rearrangement), and chromosome 1 was rearranged in four. The types and the significance of clonal chromosome abnormalities which may be present without apparent evolution toward acute leukemia or myelodysplastic syndrome in Fanconi anemia patients are discussed.

Adolescent↗
PubMed1999

Bacterial population genetics, evolution and epidemiology.

Asexual bacterial populations inevitably consist of an assemblage of distinct clonal lineages. However, bacterial populations are not entirely asexual since recombinational exchanges occur, mobilizing small genome segments among lineages and species. The relative contribution of recombination, as opposed to de novo mutation, in the generation of new bacterial genotypes varies among bacterial populations and, as this contribution increases, the clonality of a given population decreases. In consequence, a spectrum of possible population structures exists, with few bacterial species occupying the extremes of highly clonal and completely non-clonal, most containing both clonal and non-clonal elements. The analysis of collections of bacterial isolates, which accurately represent the natural population, by nucleotide sequence determination of multiple housekeeping loci provides data that can be used both to investigate the population structure of bacterial pathogens and for the molecular characterization of bacterial isolates. Understanding the population structure of a given pathogen is important since it impacts on the questions that can be addressed by, and the methods and samples required for, effective molecular epidemiological studies.

Bacteria↗
PubMed2005

Detection and typing of human papillomavirus DNA in uterine cervices with coexistent grade I and grade III intraepithelial neoplasia: biologic progression or independent lesions?

OBJECTIVE: To examine the HPV type infection of cervical cone specimens with coexistent CIN1 and CIN3 lesions, in order to define if coexistence of low- and high-grade lesions in the same cervix represent different stages of evolution in a continuing process that is caused by a single viral type or independent lesions induced by different HPV types. STUDY DESIGN: The examined material included 43 cases with coexistent CIN1 and CIN3 in the cone biopsy specimen. Detection and typing of HPV was made by RFLP-PCR. RESULTS: All CIN1 lesions were HPV positive, while three CIN3 lesions were HPV-negative. The proportion of agreement of the HPV type in the two lesions, excluding negative cases (n = 40), was 60% (95% confidence interval: 43.3-75.1). HPV 16 was the most common type in both CIN3 (56.8%) and CIN1 (46.5%). CONCLUSIONS: The so-called morphologic progression of CIN is not always synonymous with biologic progression, since many coexistent CIN lesions are caused by different HPV types, and so represent different cell clones. Clonality of coexistent CIN lesions may be implicated in the evolution of CIN as other recent studies have shown.

Adult↗
PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗
PubMed2003

Two types of ribosomal RNA genes in hybrid Trypanosoma cruzi strains.

Trypanosoma cruzi isolates can be divided into two major phylogenetic lineages-T. cruzi I and T. cruzi II. The population structure is predominantly clonal, with sexuality having no or limited influence on the evolution of the parasite. Isoenzymes and nuclear gene sequences have provided evidence that some T. cruzi strains are hybrids. Previous work of our group has shown that the putative hybrid strains designated as group 1/2 contain two types of rDNA units, corresponding to those found in T. cruzi I and T. cruzi II. In this study, the presence and transcription of the two types of ribosomal RNA (rRNA) cistrons were investigated in epimastigotes, metacyclic and tissue culture trypomastigotes of group 1/2 isolates. PCR and RT-PCR assays indicate that both types of cistrons are present in group 1/2 strains, but only type-2 genes are transcribed in all developmental stages. The structure of the promoter regions of group 1/2 was compared to reference T. cruzi I and T. cruzi II strains. In all cases, the transcription start point was mapped to a conserved A residue located approximately 1800 bp upstream the 18S rRNA gene. The distribution of rDNA clusters in chromosomal bands of group 1/2 was evaluated by pulsed-field gel electrophoresis (PFGE). The majority of type-2 rDNA genes are localized in a 1.5 Mbp band, whereas type-1 cistrons are mostly concentrated in a 1.1 Mbp band. The structural and functional studies of group 1/2 ribosomal cistrons described here may shed light on the evolutionary processes that took place during the generation of such hybrid organisms.

Animals↗
PubMed2002

Experimental models linking dendritic cell lineage, phenotype and function.

One of the important issues in dendritic cell (DC) biology today is how DC control the fate of T cells. Our data suggest that an important branch point in determining T cell fate is the decision between deletion and memory. We have previously hypothesized that this binary decision is determined by contact with DC derived from lymphoid- versus myeloid-restricted progenitors. However, the false attribution of CD8alpha expression as a reliable marker of lymphoid origin has underpinned a number of studies in which DC expressing CD8alpha did not induce deletion, thereby clouding the issue of whether deletion is indeed a function of lymphoid DC. By returning to basics, that is, functional testing of the progeny of lymphoid- and myeloid-restricted progenitors in vivo, we hope to provide clear evidence of the in vivo roles of lymphoid and myeloid DC subsets, independent of assumptions about the surface phenotypes they can assume.

Animals↗
PubMed1996

Single cell analysis of H/RS cells.

The nature of the Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin's disease (HD) is still unclear. We have studied isolated H/RS cells from four cases of lymphocytic predominance (LP) HD and six cases of nodular sclerosis (NS) HD and assayed the cells for immunoglobulin heavy chain (IgH) gene rearrangement by the polymerase chain reaction (PCR). The H/RS cells in all four cases of LPHD had rearranged their IgH gene in a polyclonal pattern. The H/RS cells of three cases of NSHD where at least a fraction of the cells expressed the B-cell marker CD20 had also rearranged their IgH gene. In two of the cases, the rearrangements were totally unrelated while in one case, two out of six rearrangements were identical in sequence indicating the presence of a clonal subpopulation amid a polyclonal background. Clonality was assessed independently in one NSHD case by determining the pattern of X-chromosome inactivation. This technique also failed to show that the H/RS cells were monoclonal. Our studies suggest that in both LPHD and NSHD, the H/RS cells may be a polyclonal proliferation at presentation and clonal populations may emerge from this polyclonal background. There is also some evidence of a correlation between the immunophenotype and the genotype of the H/RS cells. Single cell assays show great potential in elucidating the cell lineage and clonality of H/RS cells, as well as their in vivo evolution during the disease process.

Gene Rearrangement↗
PubMed1988

Red cell size heterogeneity during ontogeny.

To determine the manner in which erythrocyte changes occur during ontogeny, several red cell parameters were analyzed in fetuses, newborn infants, children, and adults. Although mean cell volume (MCV) and hemoglobin F (HbF) levels decreased as expected during in utero development, the coefficient of variation of red cell size (%CV), or red cell distribution width (RDW), increased from fetuses to newborn infants. In normal adults, the %CV was 15 (RDW was 13). The %CV in fetuses at 18-24 weeks gestation was 18, and it was 21 at term birth. High values for %CV or RDW indicate significant anisocytosis. Erythropoiesis at the time of birth is not a steady-state condition. Erythrocytes of a wide variety of sizes are present, with the appearance of new small cells on a background of older, larger red cells. This increased anisocytosis suggests that these new erythrocytes do not appear to be due to a smooth, continuous evolution of red cell size, but rather to discrete, perhaps clonal, changes.

Adolescent↗
PubMed1992

The insertion sequence IS200 fingerprints chromosomal genotypes and epidemiological relationships in Salmonella heidelberg.

In Salmonella heidelberg the copy number of the Salmonella-specific insertion element IS200 was found to vary from four to six. All strains tested contained at least one common insertion site which was serovar specific, and most strains contained three common sites. Concurrent analysis of plasmids indicated that all insertion sequence copies were chromosomally located, and also supported the equivalence of an IS200 fingerprint and clonality. Seven intra-serovar clonal lines were thereby identified. One of these was associated with human infections, including septicaemias. Another was associated with chicken as a host: all these strains also carried a unique plasmid of 23 MDa, which was typed as a member of the IncX group. The chromosomal fingerprint of a third clone showed it to be a descendant of the chicken line marked by a single IS200 transposition. One or two representatives of four other clonal lines were identified. These lines of S. heidelberg could be related by divergent evolution, and the most recent relatives conformed to a continuous branching process model of IS200 transposition. This insertion sequence provided a highly discriminatory molecular marker of the S. heidelberg chromosome, and two of the seven clonal lines so identified were associated with distinct clinical/epidemiological contexts.

Animals↗
PubMed2001

Success and virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries.

Toxoplasma gondii is a common human pathogen causing serious, even fatal, disease in the developing fetus and in immunocompromised patients. Despite its ability to reproduce sexually and its broad geographic and host range, Toxoplasma has a clonal population structure comprised principally of three lines. We have analyzed 15 polymorphic loci in the archetypal type I, II, and III strains and found that polymorphism was limited to, at most, two rather than three allelic classes and no polymorphism was detected between alleles in strains of a given type. Multilocus analysis of 10 nonarchetypal isolates likewise clustered the vast majority of alleles into the same two distinct ancestries. These data strongly suggest that the currently predominant genotypes exist as a pandemic outbreak from a genetic mixing of two discrete ancestral lines. To determine if such mixing could lead to the extreme virulence observed for some strains, we examined the F(1) progeny of a cross between a type II and III strain, both of which are relatively avirulent in mice. Among the progeny were recombinants that were at least 3 logs more virulent than either parent. Thus, sexual recombination, by combining polymorphisms in two distinct and competing clonal lines, can be a powerful force driving the natural evolution of virulence in this highly successful pathogen.

Alleles↗
PubMed2003

Stromal cell heterogeneity in fibroblast growth factor-mediated stromal-epithelial cell cross-talk in premalignant prostate tumors.

Homeostasis of normal prostate and two-compartment nonmalignant prostate tumors is dependent on two-way communication between epithelial and stromal compartments. Independence of epithelial cells on controlling instructions from stroma is a hallmark of extremely malignant epithelial cell tumors. To better understand the evolution of stromal independence during malignant progression, we performed a clonal analysis of stromal cells derived from a well-defined model of two-way stromal-epithelial cell communication that loses response to stroma during prostate tumor progression. Directionally specific signaling from stroma to epithelium contributes to homeostasis between the two compartments. Stromal cells were characterized in respect to expression and activity of isotypes of the fibroblast growth factor (FGF) family of ligands and receptors in addition to morphology and cytoskeletal markers. One stromal subtype (DTS1) exhibited a fibroblast-like morphology and did not display smooth muscle cell (SMC) alpha-actin. The other (DTS2) exhibited SMC alpha-actin and an SMC-like morphology in vitro. Both subtypes expressed FGF7 and equally low levels of FGFR2IIIc mRNA, whereas fibroblast growth factor receptor (FGFR) 1 predominated in DTS1 cells. DTS1 cells also expressed FGF10 and no detectable FGFR3, whereas the absence of FGF10 and presence of FGFR3 distinguished DTS2 cells. Epithelial cell-derived FGF9 bound to FGFR and stimulated growth of specifically FGFR3-positive DTS2 cells, not the FGFR3-negative DTS1 cells. These results demonstrate stromal cell heterogeneity in signal reception of FGF from epithelium. This correlated with potential heterogeneity in the response back to epithelial cells. Epithelium-dependent control of a stromal cell phenotype within a tumor may be a determinant of whether tumors remain in nonmalignant homeostasis or progress to malignancy.

Adenocarcinoma↗
PubMed1996

Retention of unmethylated CpG island alleles in human diploid fibroblast x fibrosarcoma hybrids expressing high levels of DNA methyltransferase.

The mechanisms underlying ectopic methylation of CpG islands in neoplastic cells are poorly understood. One determinant may be the increased expression of DNA methyltransferase (DNA MTase) observed frequently in neoplastic cells. To evaluate the role of DNA MTase overexpression in aberrant CpG island methylation, we assessed methylation of fibroblast-derived CpG islands in human diploid fibroblast x fibrosarcoma hybrid cell lines. Each of six independently derived, immortalized hybrid cell lines exhibited a high level of DNA MTase expression, comparable to that of the fibrosarcoma parental line. The methylation status of five CpG island loci, each of which was methylated extensively in the fibrosarcoma parental cells but not in the fibroblasts, was then determined in the hybrid cell lines. The patterns of methylation were consistent and highly locus dependent among the hybrid lines. Unmethylated alleles were retained stably at three loci. The parental origin of alleles could be determined at two other loci in the hybrid cells. Whereas no methylation of parental fibroblast-derived alleles of the HIC-1 locus was noted in hybrid cell lines, a marked increase in methylation of fibroblast-derived alleles of the estrogen receptor was observed in all hybrid cell lines. Therefore, despite high-level DNA MTase expression, widespread loss of unmethylated CpG islands was not observed in the hybrid cell lines. The nonrandom pattern of increased CpG island methylation in the hybrid cell lines suggests that locus-specific features and/or clonal selection, and not just DNA MTase expression, affect the evolution of ectopic methylation in neoplastic cells. Somatic cell hybrids may provide useful models for studying aberrant epigenetic events in neoplastic cells.

Alleles↗
PubMedDate not supplied

[Protein evolution rate and immunoglobulin induction].

The capacity of proteins to induce the synthesis of specific immunoglobulins was shown to be correlated with their evolution rate. This correlation can be understood in terms of the clonal-selectional theory. The characteristic correlation parameter is the number of differences in the amino acid sequences between the immunogenic protein and the homological protein of the immunized animal. The above correlation was traced most clearly for the evolutionary conservative proteins.

Actins↗
PubMed1999

Semiquantitative analysis of residual disease in patients treated for adult T-cell leukaemia/lymphoma (ATLL).

Many adult T-cell leukaemia/lymphoma (ATLL) patients who respond to induction treatment, then relapse. Knowing the clonality pattern of residual tumourous clones during treatment could help understand disease evolution and aid therapeutic decisions. We developed a sensitive and semi-quantitative molecular analysis of these clones in ATLL patients. DNA samples from PBMCs derived from eight ATLL patients were studied over time by quadruplicate linker mediated PCR (LMPCR) amplification of HTLV-1 integration sites. Patients were treated with combination chemotherapy, zidovudine-interferon-alpha and/or by peripheral stem cell transplantation or allogeneic bone marrow transplantation. Persistence of tumourous clones at a high frequency (>1/300 PBMCs) was frequently observed, even in complete responders, and was invariably correlated with relapse and/or poor outcome. Fluctuation in the frequency of some tumourous clones was observed with evidence for clonal change under treatment in one patient, indicating that treatment of ATLL can result in the selection of resistant clones. Finally, allogeneic bone marrow transplantation (BMT) using an HTLV-1 infected sibling as donor was found to be associated with long-lasting disappearance of tumourous clones and a possible cure of the disease. Long-term persistent clonal expansion of circulating HTLV-1 bearing T cells which derived from the donor bone marrow was evidenced in this patient. In conclusion, variable success in treatment of ATLL is probably due to the clonal heterogeneity which results in the selection of resistant clones. Semi-quantitative assessment of residual disease (RD) through LMPCR may predict treatment failure. Accordingly, additional therapy may be tailored to the clonality pattern observed after first-line therapy.

Adult↗