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Results for “clonal evolution”

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PubMed2001

Oligoclonal expansion of alphabeta T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with abnormal karyotypes.

We observed a fatal case of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) with an abnormal karyotype. Increased levels of alphabeta T cells of the patient were investigated using an inverse polymerase chain reaction (PCR) of the T-cell receptor variable region gene, followed by Jbeta-PCR and single-strand conformation polymorphism (SSCP) to confirm the clonality of specific alphabeta-T cell subsets. A high frequency (>15%) was recognized in Vbeta9 at onset, but not in any Vbeta and Valpha families 2 weeks after chemotherapy. High levels (>20%) of some Jbeta genes were detected in all Vbeta families investigated, and the predominant bias of the Jbeta2 gene relative to the Jbeta1 gene (86.1% versus 13.9% at onset, and 77.4% versus 23.5% after chemotherapy) was recognized in pan-alphabeta T cells. When each Vbeta-Jbeta fragment was compared among the samples at onset and after chemotherapy by SSCP analysis, several distinct bands were observed that indicate a clonal evolution. Thus, the findings suggest that some of the alphabeta T cell clones could be associated with abnormal karyotypes in EBV-HLH. The present findings provide molecular evidence of the presence of oligoclonal T cells in pan-alphabeta-T cells and clonal evolution during a short clinical course in EBV-HLH with abnormal karyotypes.

Child↗

PubMed2003

Cytogenetic studies in patients on imatinib.

With the introduction of imatinib (Gleevec) (formerly STI571) for the treatment of chronic myeloid leukemia (CML), the various diagnostic methods used to monitor patients must be re-evaluated. Conventional cytogenetics has been the established method for follow-up of patients treated with interferon-alpha (IFN-alpha), and the prognostic value of major and complete cytogenetic remission was demonstrated in a number of studies. In patients on imatinib, these endpoints will likely remain valid, although longer observation is required. Cytogenetic remission as a time-dependent variable may aid risk stratification early on. Clonal evolution, ie, the presence of cytogenetic abnormalities in addition to the Philadelphia (Ph) chromosome, may provide important prognostic information as to the likely response to imatinib in all phases of CML but must be interpreted within the context of other disease characteristics. In some patients, clonal evolution is related to imatinib resistance. Information regarding the impact of specific types of additional cytogenetic abnormalities is still limited. Surprisingly, nonrandom karyotypic abnormalities have also been noted in the Ph-negative cells of some patients in cytogenetic remission. This is a novel phenomenon whose causality and prognostic implications require thorough and systematic evaluation.

Benzamides↗

PubMed2001

PCR techniques for clonality assays.

Clonal overgrowths represent the hallmark of neoplastic proliferations, and their demonstration has been proved useful clinically for the diagnosis of malignant lymphomas based on the detection of specific and dominant immunoglobulin and/or T-cell receptor gene rearrangements. Nonrandom genetic alterations can also be used to test clonal expansions and the clonal evolution of neoplasms, especially analyzing hypervariable deoxyribonucleic acid (DNA) regions from patients heterozygous for a given marker. These tests rely basically on the demonstration of loss of heterozygosity (LOH) resulting from either hemizygosity (nonrandom interstitial DNA deletions) or homozygosity of mutant alleles observed in neoplasms. LOH analyses identify clonal expansions of a tumor cell population, and point to monoclonal proliferation when multiple and consistent LOH are demonstrated. Based on the methylation-related inactivation of one X chromosome in female subjects, X-linked markers (e.g., androgen receptor gene) will provide clonality information using LOH analyses after DNA digestion with methylation-sensitive restriction endonucleases. Therefore, both non-X-linked and X-linked analyses give complementary information, related and not related to the malignant transformation pathway respectively. Applied appropriately, these tools can establish the clonal evolution of tumor cell populations (tumor heterogeneity), identify early relapses, distinguish recurrent tumors from other metachronic neoplasms, and differentiate field transformation from metastatic tumor growths in synchronic and histologically identical neoplasms.

Clone Cells↗

PubMed1978

Down's syndrome and leukemia: mechanism of additional chromosomal abnormalities.

There is an increased incidence of acute leukemia in patients with Down's syndrome patients have a trisomy-21 chromosomal pattern, and chromosomal abnormalities can be seen in acute leukemia. It is possible that the increased incidence of acute leukemia in Down's syndrome persons may be due in part to their chromosomal abnormalities. Such abnormalities, some appearing in a stepwise clonal evolution, were found in five Down's syndrome patients, four with acute leukemia and one with abnormal regulation of leukopoiesis. Morphological abnormal chromosomes were also found in three patients. These chromosomal abnormalities are similar to those seen in non-Down's syndrome leukemic patients. There is suggestive evidence for clonal evolution hypothesis of luekemogenesis in non-Down's syndrome patients. The abnormal chromosomal pattern reported in our Down's syndrome patients could be the result of nondisjunction in mitosis, and leukemia may be the phenotypical expression of this nondisjunction.

Acute Disease↗

PubMed2003

Comprehensive cytogenetic analysis including multicolor spectral karyotyping and interphase fluorescence in situ hybridization in lymphoma diagnosis. a summary of 154 cases.

Cytogenetic analysis including multicolor spectral karyotyping (SKY) and interphase fluorescence in situ hybridization (FISH) was performed on 154 consecutive cases with suspected lymphoma. The cytogenetic results were reviewed in correlation with the final pathologic diagnosis. A diagnosis of lymphoma was established in 94 cases, with 16 Hodgkin lymphomas and 78 non-Hodgkin lymphomas (NHL). Cytogenetic results were obtained in 63 NHLs (81%); 61 of those showed abnormal karyotypes (97%). The t(14;18) or IGH-BCL2 fusion was detected in 83% (20/24) of follicular lymphomas and in 57% (12/21) of diffuse large B-cell lymphomas (DLBCL). The application of interphase FISH and SKY has contributed to a high detection rate of t(14;18) in DLBCLs. This study showed that genes at 1q25, 3p21, 3q21, 5q31, 6p23, 7q22, 8q11 approximately q12, 9q34, 11q23, 12q13, and 19q13.1 may have been involved as the less common changes in follicular lymphoma and DLBCL. Comparison of the recurrent secondary aberrations in the groups of follicular lymphoma and DLBCL revealed a pattern of clonal evolution from the changes rea(1)(p36), del(6q), +7, +12 or dup or trp(12)(q13q22), +der(18)t(14;18), and +21 in follicular lymphoma to the changes rea(1)(p36), del(6q), +6, +7, +9, rea(11)(q23), +12, -13 or del(13(q12q14), +18, +21, and +X in DLBCL. The clonal evolution of the secondary aberrations is thought to contribute to the progression of the disease. About 90% (16/18) of other types of NHL had abnormal karyotypes showing specific translocations or gene rearrangements consistent with the pathologic diagnosis. A comprehensive cytogenetics approach including SKY and interphase FISH using probes for specific genes, such as IGH, BCL2, CCND1, and ALK, is a very useful ancillary diagnostic tool for lymphomas. The combined approach also led to the identification of t(2;19)(p23;q13.1) as a new variant of t(2;5)(p23;q35) in a case of Ki-1-positive anaplastic large cell lymphoma with a null cell phenotype.

Chromosome Aberrations↗

PubMed1986

Chromosomal aberrations in lymphocyte and fibroblast cultures of patients with the sporadic type of Kaposi sarcoma.

Numerical and structural chromosomal aberrations were found in metaphases from lymphocyte cultures from Sardinian patients with the sporadic type of Kaposi sarcoma, and also in fibroblasts derived from cultured biopsies of the tumoral lesions. In several cases there was evidence of clonal evolution of some of the chromosomal aberrations. The chromosomes most frequently involved in numerical aberrations were 10, 13, 15, 22 and the X and Y chromosomes, and those most frequently involved in translocations and deletions were 7, 13, 15, 22 and the X chromosomes. The hypothesis is made that in Kaposi sarcoma the chromosomal instability and clonal evolution in vivo could be modulated by the immunologic situation peculiar to the condition.

Aged↗

PubMed2007

Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia.

BACKGROUND: The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT. PROCEDURE: In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004. RESULTS: In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. CONCLUSIONS: We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary.

Adolescent↗

PubMed2006

Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil.

Severe aplastic anaemia (SAA) can be successfully treated with immunosuppressive therapies or haematopoietic stem cell transplantation (HSCT). Response rates with horse anti-thymocyte globulin (h-ATG) plus ciclosporin (CsA) are about 60-70%, and robust responders have an excellent long-term survival. We introduced a third immunosuppressive agent to standard h-ATG/CsA, mycophenolate mofetil (MMF), in an attempt to improve the response rate and survival, and to decrease the relapse rate and clonal evolution to myelodysplasia. A total of 104 consecutive patients with SAA were treated with h-ATG/CsA/MMF between May 1999 and June 2003 at the National Institutes of Health Clinical Center. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 d from ATG. Nine patients showed evidence of clonal evolution following ATG. After a median follow up of 42 months, the median survival among responders was not reached and among non-responders was 58 months. Over half of the relapses occurred during MMF administration. Despite a strong theoretical rationale for its use, MMF did not result in the improvement of response or relapse rates when compared with historical standard h-ATG/CsA.

Adolescent↗

PubMed1996

Chronic myelogenous leukemia in blast crisis: retrospective analysis of prognostic factors in 90 patients.

Ninety patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis were reviewed to identify significant prognostic associations. At diagnosis of blast crisis the main clinical, laboratory, and cytogenetic data were recorded and evaluated for prognostic significance. At the time of the analysis 89 patients had died, with a median survival of 11 weeks from diagnosis of blast crisis. Patient characteristics demonstrated in the univariate analysis to have significant association with shorter survival were: thrombocythemia, leukocyte count above 20 x 10(9), Karnofsky index < 50%, nonlymphoid blast cell morphology, cytogenetic clonal evolution, the presence of a double Philadelphia chromosome or trisomy 8, and no response to therapy. In 17 of 59 patients (29%) evaluable for response to therapy a complete or partial remission was achieved. These responders had a significantly longer median survival (25 weeks) as compared with nonresponders (9 weeks). Response to therapy was significantly better in lymphoid blast crisis and in patients without clonal evolution. In a multivariate analysis containing all significant variables of the univariate analysis two parameters retained their prognostic significance: response to therapy and trisomy 8. In spite of the short overall survival in blast crisis, the determination of prognostic factors may be a useful tool for the clinician planning therapy, especially new therapeutic approaches.

Adult↗

PubMed1984

Clinicopathological characteristics of acute lymphoblastic leukemia with the 4;11 chromosome translocation.

Analysis of the bone marrow karyotype in 109 consecutive untreated patients with acute lymphoblastic leukemia (ALL) by the G-banding technique revealed the presence of a translocation between specific sites on the long arms of chromosomes 4 and 11, [t(4;11) (q21;q23)] in 3 adults and 2 children. Splenomegaly was present in all patients, marked leukocytosis in 4, and retinal hemorrhages in the absence of significant mucocutaneous bleeding in 3. Complete remission defined by conventional morphological criteria was achieved with combination chemotherapy in all instances, but the duration of remission was brief in 3. Three patients were studied in relapse, and clonal evolution was found to have occurred in 2. Analysis of our data in conjunction with other published reports suggests this specific karyotypic abnormality characterizes a small subgroup of ALL in which there is a strong association with recognized clinical and laboratory indices of poor prognosis, in particular its frequent occurrence in children under the age of 2.5 yr. There is a propensity to undergo clonal evolution, and the possibility exists that such a development is associated with poor prognosis.

Adolescent↗

PubMed2000

Somatic mutation of the 5' noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma.

Follicular lymphoma (FL) is a B cell non-Hodgkin's lymphoma (NHL) that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5' noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of the BCL-6 gene alterations in the histological transformation and clonal progression of FL, we analyzed serial biopsy specimens from 12 patients with FL. Two cases of FL showed no histological alteration in the second biopsy, and 10 cases of FL showed morphological transformation to DLCL in the second biopsy. Southern blot analysis was used to detect rearrangement of the BCL-6 gene, polymerase chain reaction-single strand conformation polymorphism and sequence analysis were performed for identification of mutations in the 5' noncoding region of the BCL-6 gene, and immunohistochemical analysis was applied to reveal the BCL-6 protein expression. No BCL-6 gene rearrangement was detected in any of the samples, but a total of 58 mutations were found in the 5' noncoding region of the BCL-6 gene in seven cases. In five cases, both the FL and the clonally related FL or DLCL, and in two cases only the DLCL samples were mutated. The mutations were identical in multiple biopsy specimens of FL that did not show morphological transformation. In six patients where FL cells underwent morphological transformation, considerable intraclonal sequence heterogeneity was observed, indicating an ongoing type of somatic mutation. Based on the pattern of shared and nonshared mutations, the genealogical relationship of neoplastic clones could be established. In all of these cases, the histological transformation of FL was associated with the emergence of a subpopulation marked by new sites of mutations in the BCL-6 5' noncoding sequences. In three of these six cases, the histological transformation is also associated with the reduced expression of the BCL-6 protein. These findings demonstrate that mutation of the 5' noncoding region of the BCL-6 gene developed in the clonal evolution of FL, and at different time points in the lymphoma evolution different clonotypes dominate.

5' Untranslated Regions↗

PubMed2025

Genomic characteristics and prognostic correlations in Chinese multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of abnormal clonal plasma cells in the bone marrow. The heterogeneity in Chinese MM populations remains underexplored. METHODS: We conducted whole-exome sequencing (WES) on 241 tumor samples, complemented by RNA sequencing (RNA-seq) on 131 samples from 212 Chinese MM patients. RESULTS: We identified a novel mutational signature and analyzed molecular differences between newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. NFKBIA mutations were notably more frequent in NDMM patients compared to the MMRF-COMMPASS cohort (4/50 vs 22/937, p = 0.048), with additional recurrent mutations in several genes like TTN, IGLL5 and SYNE1. In RRMM patients, UBR5 mutations were more prevalent (4/24 vs 0/50, p = 0.01), alongside frequent mutations in OBSCN, CACNA1H, and HSPG2. Clonal evolution was assessed through multiple time points and locations, identifying genes potentially linked to circulating plasma cell formation. Cox regression analysis revealed that age and mutations in OBSCN and RB1 were significant predictors of progression-free survival (PFS) in NDMM patients. Additionally, albumin, β2-microglobulin, and RB1 mutations were correlated with overall survival (OS). CONCLUSIONS: In summary, we characterized the genomic landscape of MM in diverse Chinese populations, confirmed clonal evolution, and identified prognostic genes.

Adult↗

PubMed1988

Clinical transformation of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is usually stable over months to years however a small proportion of cases may transform to more aggressive forms. These transformations include diffuse lymphoma (Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia and multiple myeloma. There are a variety of techniques to determine whether the transformation represents a clonal evolution of the original CLL or an independent disease. These include cytogenetic analysis, immunoglobulin gene rearrangement by Southern blot analysis, and anti-idiotypic antibodies. While identity can be determined by gene rearrangement and anti-idiotypic antibodies, lack of identity can occur because of somatic mutation within a single clone. Thus, even with optimal techniques it is difficult to definitively exclude lack of identity in some instances. In most cases where transformation has taken place, definitive studies were not performed. In instances where detailed data are available, most do not suggest clonal evolution. Further studies are needed to allow definite conclusions.

Cell Transformation, Neoplastic↗

PubMed1992

Evolution of clonality and invasive behavior of Epstein-Barr virus immortalized lymphoblastoid cell lines in SCID mice brains.

BACKGROUND: Recently established Epstein-Barr virus immortalized lymphoblastoid cell lines express polyclonal immunoglobulins, are diploid, and grow into invasive tumors when injected intracerebrally into mice with severe combined immunodeficiency (SCID). It is unclear whether clonal selection of neurotropic cell lines occurs during long-term growth in the brain and the effect of this selection on brain invasiveness. EXPERIMENTAL DESIGN: Epstein-Barr immortalized lymphoblastoid cell lines from a normal Epstein-Barr negative donor were serially passaged seven times intracerebrally within groups of SCID/SCID CB 17 mice. Each cell line was injected into five or more animals during each passage. Clonality of the rescued cell lines, genotype, and brain invasiveness were examined. RESULTS: All mice developed extensive intracerebral lymphoproliferative disease within 10-18 days after injection. Intracerebral, subarachnoid, intraventricular, and perivascular lymphoid lesions were noted. Infiltrates were similar in all animals studied regardless of the passage number. Clonal B cell populations were detectable in lesions after the first passage by Southern blot hybridization using JH probe. Immunohistochemically, polyclonal tumors were seen initially, but after the fourth passage, monoclonal cytoplasmic immunoglobulin was predominantly expressed by all tumors. Minor bands seen in the early passages disappeared subsequently. Random chromosomal abnormalities appeared in the rescued cell lines after the third passage; however, after the sixth passage, the abnormalities became more consistent. Clonability in agarose was very low initially in both cell lines and increased significantly after the sixth passage. CONCLUSIONS: These experiments demonstrate that within the immunoprivileged conditions of the SCID mouse brain, the evolution of Epstein-Barr immortalized lymphocytes from polyclonal to oligo- and monoclonal cell lines with chromosomal abnormalities occurs very early. This evolution is not paralleled by increased invasiveness in vivo.

Animals↗

PubMed2001

[Promoter hypermethylation during tumor progression: quantitative analysis employing kinetic PCR].

The methylation of cytosine residues in the promoter region of tumour-suppressor genes is now widely recognised as an alternative mechanism of gene inactivation in cancer. To address the question whether promoter methylation is an early event in the process of malignant transformation and whether quantitative changes are occurring during clonal evolution we developed a new assay for the measurement of cytosine methylation, which could also be applied to laser-microdissected archival specimens. We first improved the bisulfite conversion of genomic DNA in order to analyse cells isolated from archival tissue sections by laser-assisted microdissection. Analysing the methylation of key regulatory genes in archival specimens (n = 38) we could demonstrate that aberrant promoter hypermethylation is an early event during breast cancer development and changes quantitatively and in a gene-specific manner during progression. This novel methodological approach allows the morphology-guided quantitative analysis of changes in the methylation pattern during the clonal evolution of tumour cells. Quantitative differences detected by this assay will offer new insights into early steps in carcinogenesis and tumour cell heterogeneity.

DNA Methylation↗

PubMed1987

Hybrid leukaemia of T cell and myeloid lineages: cytogenetic distinction from second (induced) malignancy.

The therapeutic and prognostic implications of relapse and clonal evolution of leukaemia are substantially different from those of secondary (induced) malignancy. This report documents the case of a patient who presented with apparent acute non-lymphocytic leukaemia (ANLL) following therapy for acute (T-cell) lymphoblastic leukaemia (ALL) 4 years previously. Morphologically and cytochemically the cells were of myeloid type, but the cell markers showed a T cell lineage. Cytogenetic studies confirmed that this was a relapse of T cell ALL with a phenotypic change, rather than a second malignancy induced by chemotherapy. A 14q deletion present at initial diagnosis recurred at relapse, with the addition of cells with complete deletion of chromosome 14, indicating clonal evolution.

Child↗

PubMed1994

Cytogenetic intratumor heterogeneity in soft tissue tumors.

Multiple (two to seven) samples, obtained from the same surgical specimen or at different occasions, were analyzed in 54 benign and malignant soft tissue tumors, to investigate cytogenetic clonal evolution. In 28 tumors only normal karyotypes were found. Ten tumors had abnormal karyotypes, but were noninformative, most often due to a high level of karyotypic complexity or great cell-to-cell variation. Sixteen tumors were informative: four (leiomyosarcoma, liposarcoma, malignant Schwannoma, and a benign mesenchymal tumor, probably leiomyoma) had identical karyotypes in different samples, whereas the remaining 12 tumors (seven malignant fibrous histiocytomas [MFH], two leiomyosarcomas, two liposarcomas, and one synovial sarcoma) displayed intersample heterogeneity. Also, intrasample heterogeneity was detected; more than one clone was found in 21 of 73 samples with aberrations from 26 tumors. The different clones were related in all cases except two. In seven cases, samples from different occasions were studied, and clonal evolution could be evidenced in five of them, whereas in two cases the karyotypes remained unchanged. The results indicate that the acquisition of ring chromosomes is an early event in the development of MFH and possibly also pleomorphic liposarcoma. The findings, together with previous data, also indicate that rearrangements of 19p13 are late events in the progression of pleomorphic sarcomas. The overall conclusion from this study is that cytogenetic heterogeneity is common in soft tissue tumors, and that this might influence the evaluation of cytogenetic and molecular genetic findings.

Adult↗

PubMed1988

Characteristics of accelerated disease in chronic myelogenous leukemia.

Determination of the characteristics of accelerated disease in chronic myelogenous leukemia (CML) helps in individual prognostication, and in the introduction and analysis of investigative approaches based on risk-benefit ratios. The outcome of 357 patients with Philadelphia chromosome-positive CML was analysed from the time of development of suspected features of accelerated disease. Median survivals shorter than 18 months were associated with the appearance of any of the following: cytogenetic clonal evolution; extramedullary disease; peripheral blasts greater than or equal to 15%, peripheral blasts and promyelocytes greater than or equal to 30%, or peripheral basophils greater than or equal to 20%; platelet count less than 1.0 X 10(5)/microliters; marrow blasts greater than or equal to 15%, marrow blasts and promyelocytes greater than or equal to 30%, or marrow basophils greater than or equal to 20%. Relative hazard ratios, or risk of death per unit time, were calculated based on the relative survivals of patients who did or did not develop the particular feature of accelerated disease, after accounting for the time to development of the characteristic. Further analysis identified five features that have additive independent prognostic importance: cytogenetic clonal evolution; peripheral blasts greater than or equal to 15%; peripheral basophils greater than or equal to 20%; peripheral blasts and promyelocytes greater than or equal to 30%; and thrombocytopenia. By providing an objective estimate of prognosis in accelerated disease, the model identifies patients in need of different therapeutic interventions before the development of blastic crisis.

Follow-Up Studies↗