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PubMed2000

Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity.

Carcinosarcomas of the uterus, ovaries, and fallopian tubes are highly aggressive neoplasms with incompletely understood histogenesis. Although recent immunohistochemical, cell culture, and molecular genetic studies all favor these cancers to be monoclonal in origin, the extent of intratumoral genetic heterogeneity in these tumors with divergent histology has not been reported previously. For this study, we microdissected a total of 172 carcinomatous or sarcomatous foci from 17 gynecological carcinosarcomas and analyzed allelic status with 41 microsatellite markers on chromosomal arms 1p, 1q, 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11p, 11q, 13q, 16q, 17p, 17q, 18q, and 22q. With the exception of a single case with microsatellite instability, we found shared allelic losses and retentions among multiple individually dissected foci of each case, strongly supportive of the concept of a monoclonal origin for these neoplasms. In eight of these cases, we also found heterogeneous patterns of allelic loss at limited numbers of chromosomal loci in either the carcinomatous or sarcomatous components of the neoplasms. These heterogeneous patterns of allelic losses were consistent with either genetic progression or genetic diversion occurring during the clonal evolution of these neoplasms. In two cases, we found the specific patterns of genetic progression to be consistent with sarcomatous components of the neoplasms arising from carcinomatous components. We conclude that most of the gynecological carcinosarcomas have a monoclonal origin, and that genetic progression and diversion parallel the development of divergent phenotypes in these tumors. Because phenotypically divergent areas of the tumors share numerous genetic alterations, this divergence most likely occurs relatively late in the evolution of these tumors.

Carcinosarcoma↗
PubMed2001

Clonal evolution of a radon-induced rat lung tumor.

Radon gas may represent a source of pulmonary radio-contamination either in mine or in domestic conditions. Since epidemiological studies are controversial, as long as biological markers of the exposure to such agents will not be identified, the question will remain open. We have previously shown a direct dose-dependent relationship between lung cancer occurrence and radon inhalation of rats. In this study, we report a cytogenetic study of a radon-induced rat lung tumor. Chromosome banding and chromosome specific paintings were performed on cultures of both fresh and xenografted tumors. We found by analyzing 17 sub-clones that all karyotypes presented a translocation involving rat chromosomes (RNO) 8 and 20, and a terminal deletion of RNO 15p suggesting a monoclonal origin of this tumor. RNO 15 is homologous to numerous human chromosomes (HSA), in particular to HSA 3p14.2, 3p22-p24.1 and 3p24.2-p24.3, this human chromosome being frequently lost in human lung carcinomas. Besides sharing chromosome alteration involving common features with those found in human lung cancer, this rat lung carcinoma represents a useful model to study tumor progression with respect to clonal evolution.

Animals↗
PubMed2000

Clonal evolution in a primary cutaneous follicle center B cell lymphoma revealed by single cell analysis in sequential biopsies.

B cell neoplasias descending from germinal center cells harbor the hallmark of intraclonal diversity resulting from ongoing mutation in the variable parts of their immunoglobulin-encoding genes. To characterize a primary cutaneous follicle center B cell lymphoma in more detail, we analyzed the respective VH and VL genes in single cells mobilized from four sequential biopsies, three taken from the skin and one obtained after internal dissemination from a retrobulbar infiltrate. The lymphoma cells were found to contain V5-51/D6-12/JH5b (heavy chain) and A27/Jkappa2 (light chain) gene rearrangements detected on both the genomic and the transcriptional level. To provide an accurate mutation analysis, the specific VH gene counterpart (V5-51UK) was cloned from the patient's germline. Analyzing 226 single cells, we found: (i) complete nucleotide identity when VH and VL genes of lymphoma cells from one particular biopsy were compared among each other; (ii) intraclonal diversity due to ongoing mutation comparing the sequences obtained from sequential biopsies; (iii) both VH and VL genes to be highly mutated. Deducing from the sequence data, we propose a scenario of the clonal evolution of the B cell tumor in this patient. From the molecular-biological point of view, this primary cutaneous follicle center B cell lymphoma shows the features of a germinal center cell lymphoma. To draw this conclusion from single cell PCR data, however, a sample of sequential biopsies had to be analyzed.

B-Lymphocytes↗
PubMed2003

Parity between kinetoplast DNA and mini-exon gene sequences supports either clonal evolution or speciation in Trypanosoma rangeli strains isolated from Rhodnius colombiensis, R. pallescens and R. prolixus in Colombia.

Trypanosoma rangeli are kinetoplastid protozoa which have been largely recognized and defined in several Latin American countries in relation to T. cruzi, because the two trypanosome species are frequently found in mixed infections in triatominae vectors, humans and a variety of wild and domestic mammals. We report the molecular characterization of 18 T. rangeli strains isolated from the salivary glands of naturally infected Rhodnius colombiensis, R. pallescens and R. prolixus by using two independent set of molecular markers. kDNA and mini-exon amplification indicated dimorphism within both DNA sequences: KP1, KP2 and KP3 or KP2 and KP3 products for kDNA mini-circles and 380 or 340bp products for the mini-exon. One of two associations was observed within individual strains: KP1, KP2 and KP3 kDNA products with the 340bp mini-exon product and the KP2 and KP3 kDNA products with the 380bp mini-exon product. Independent mitochondrial and nuclear molecular markers showed a clear division of T. rangeli into two major phylogenetic groups associated with specific vectors in Colombia and in other Latin America countries. These results support either clonal evolution or speciation in T. rangeli populations, probably derived as a secondary adaptation to their parasitic condition in triatomine vectors.

Animals↗
PubMed1990

[Mixed blast crisis with the cytogenetic evidence of three clonal evolutions].

A 46-year-old man was diagnosed as having chronic myelogenous leukemia (CML) in chronic phase in Dec. 1985. In Dec. 1987, anemia and leukocytopenia progressed, and the percentage of blast cells increased in the bone marrow. The blast cells were lymphoblastoid and positive for TdT. It was treated as a lymphoid crisis with vincristine and prednisolone, and complete remission was achieved. However, the blasts (11%) were observed in the bone marrow in Mar. 1988, and the chromosomal analysis revealed 46, XY, t (2q-; 11q+), t (9q+; 22q-) in 13 out of 20 cells. In June, the percentage of the blasts increased again, but chromosomal analysis showed a different karyotype, 46, XY, t(2p-; 11p+), t(9q+; 22q-) which was observed in 9 out of 10 cells. Then, myeloblastoid cells increased rapidly in spite of the chemotherapy in Dec. 1988. The chromosomal analysis showed 46, XY, 2p-, 7q-, 9q+, 11p+, 22q- in all analyzed cells. The rearrangement of the bcr gene could be detected by the Southern blotting. The blasts were positive for CD7, CD11, CD13, CD33, CD36, CD41 and CD42, suggesting that the blasts had the surface phenotypes of both myeloid and megakaryocytoid-lineage. This is a case with the mixed blast crisis that changed from the lymphoid to the myelo-megakaryocytoid in nature, in which three clonal evolutions were observed during the clinical course.

Antigens, CD↗
PubMed1995

Clonal evolution of an immunoblastic type non-Hodgkin's lymphoma with der(6)t(1;6)(q11;p11) as its primary cytogenetic abnormality.

Recurrent pleural effusions from a 45-year-old man who was diagnosed as having non-Hodgkin's lymphoma of immunoblastic type were studied cytogenetically. The majority of the metaphases were tetraploid, but there were also lymphoma cells observed with pseudodiploid chromosome constitutions. Cytogenetic analysis by G-banding revealed the existence of at least two cell populations. The karyotype of the minor pseudodiploid clone, which exhibited partial trisomy of 1q11qter and monosomy of 6p11pter as sole abnormalities, was 46,XY,der(6)t(1;6)(q11;p11). The karyotype of the major clone was 92,XXYY,-1,der(6)t(1;6)(q11;p11)x2, +9. The ancestral diploid clone, carrier of the balanced translocation involving chromosomes 1 and 6, was not observed even in the first pleural effusion harvest. The high proportion of tetraploid cells in the recurrent effusions was an indication that these cells were favorably selected in the environment of the somatic cavity. Our cytogenetic findings suggest that partial trisomy of 1q may be a crucial secondary chromosomal abnormality in highly malignant non-Hodgkin's lymphoma. This genetic imbalance was predetermined from the primary abnormality and may be responsible for further tumor progression, as suggested from the clonal evolution in this particular case and, therefore, may be associated with the aggressive biologic behavior of malignant cells.

Chromosome Aberrations↗
PubMed2000

Interstitial deletion of the short arm of chromosome 12 during clonal evolution in myelodysplastic syndrome with t(5;12)(q13;p13) involving the ETV6 gene.

We report here a 65-year-old man with a myelodysplastic syndrome (MDS), refractory anemia with excess of blasts. He had received chemotherapy with tegafur for renal carcinoma. Chromosome analysis of bone marrow cells revealed complex karyotypes; del(5)(q13) was observed in all 20 metaphase spreads, and two related aberrations, add(12)(p11) and add(12)(p13), were detected in 13 and 7 cells, respectively. Fluorescence in situ hybridization (FISH) analysis with chromosome-specific DNAs revealed that these alterations originated from a reciprocal translocation (5;12)(q13;p13). Therefore, del(5)(q13), add(12)(p11), and add(12)(p13) were revised as der(5)t(5;12)(q13;p13), der(12)del(12)(p11p13)t(5;12)(q13;p13), and der(12)t(5;12)(q13;p13), respectively. Fluorescence in situ hybridization with a series of cosmid probes spanning the ETV6 gene showed that the 12p13 breakpoint on the der(12)t(5;12)(q13;p13) was located in intron 1, but the exon 1 signal was deleted. Our results suggest that a fusion gene was generated between the 5'-end of an unidentified partner at 5q13 and the 3'-end of ETV6 by t(5;12)(q13;p13), and that the interstitial deletion (12)(p11p13) occurred following t(5;12) during clonal evolution. del(12)(p11p13), including the rearranged ETV6 gene, may be implicated in the progression of MDS.

Aged↗
PubMed1999

Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution.

Invasive squamous carcinoma of the uterine cervix (CC) arises from sequential progression of low-grade (L) and high-grade (H) squamous intraepithelial lesions (SILs). In clinical observations, these lesions are frequently found as synchronous multiple foci. The nature and evolutionary mechanism of these lesions are largely unknown. We have performed allelotyping of three 3p markers (at 3p14, 3p22-24, and 3p25) on 22 LSILs and 15 HSILs microdissected from patients with multiple (n = 21) or uniform (n = 6) cervical lesions. The results were analyzed together with our previous allelotyping of 57 deeply invasive CCs. Loss of heterozygosity at one of the three markers was observed in 23%, 27%, and 31 % of LSILs, HSILs, and CCs, respectively. Frequent and early allelic loss was noted (in 30% of LSILs and 50% of HSILs) at 3p14, which may harbor tumor suppressor genes involved in early stages of cervical carcinogenesis. A high frequency of microsatellite alteration (MA) was found in LSIL (41%) and HSIL (67%) but not in CC (5.3%). In particular, MA was more frequently found in low-grade lesions in association with invasive cancers (75%, 6/8) than in those associated with SILs (29%, 4/14) (P < 0.05). Together with the finding of a monoclonal origin of premalignant and malignant cervical lesions, the present results allow us to propose a model of local field effect of genomic instability that progressively affects the clonal evolution of SIL of uterine cervix.

Carcinoma in Situ↗
PubMed2005

CD34+CD7+ leukemic progenitor cells may be involved in maintenance and clonal evolution of chronic myeloid leukemia.

PURPOSE: We analyzed CD34+ cells coexpressing CD7 in chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase (AP) to clarify their role in progression or regression of the disease during treatment. EXPERIMENTAL DESIGN: Enumeration of CD34+CD7+ cells was done on bone marrow nucleated cells from normal donors and CML patients. Fluorescence in situ hybridization analysis was done on sorted CD34+CD7+and CD34+CD7- cells to examine the occupancy rate of each fraction by BCR-ABL+ cells with or without additional cytogenetic abnormalities. RESULTS: The proportion of CD34+CD7+cells was significantly affected by the treatment outcome and/or the disease status as follows: 20.5 +/- 10.4% in normal donors (n = 22), 18.1 +/- 10.2% in CP with major cytogenetic response (n = 14), 53.0 +/- 12.9% in CP at diagnosis (n = 18), 55.0 +/- 15.8% in CP with minor or no cytogenetic response (n = 28), and 70.2 +/- 18.1% in AP (n = 6). The proportion of CD34+CD7+cells decreased in parallel with cytogenetic improvement in individual patients. In six untreated CP patients, the ratio of BCR-ABL+ cells was comparable between each fraction. In three patients with major cytogenetic response, the ratio of BCR-ABL+ cells was remarkably lower in CD34+CD7- cells than in CD34+CD7+cells. In three AP patients with additional cytogenetic abnormalities, extra signals were detected at a much higher rate in CD34+CD7+ cells than in CD34+CD7- cells. CONCLUSIONS: Our results suggest that CD34+CD7+ cells may be involved in maintenance and clonal evolution of BCR-ABL+ cells in CML.

Adolescent↗
PubMed1999

ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia.

Methylation of the proximal promoter of the ABL1 oncogene is a common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In this study we queried whether both the Ph'-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally, whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. By contrast, in clinical samples from patients at advanced stages of disease, both methylated and unmethylated promoter alleles were detectable. To distinguish between allele-specific methylation and a mixed cell population pattern, we studied the methylation status of ABL1 in colonies derived from single hematopoietic progenitors. Our results showed that both methylated and unmethylated promoter alleles coexisted in the same colony. Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. Both cell lines and clinical samples from acute-phase CML showed nearly uniform hypermethylation along the promoter region. Finally, we showed that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. Our data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML.

Alleles↗
PubMed1994

A potential role for antigen selection in the clonal evolution of Burkitt's lymphoma.

Burkitt's lymphoma (BL) is a monoclonal lymphoproliferative disorder characterized by the presence of specific chromosomal translocations that involve the c-myc proto-oncogene. Two subtypes of BL exist (endemic and sporadic) that differ in the prevalence of EBV genome expression. Although EBV infection may promote cellular proliferation in endemic BL, little is known about the forces that drive clonal expansion and evolution in the majority of EBV-negative sporadic BL. This study on an EBV-negative sporadic BL cell line derived from an AIDS patient provides evidence that antigenic stimulation may play a role in the development and/or expansion of such tumors. This cell line (BRG-P) contained a series of cellular clones that elaborated both IgM and IgA. Southern blot analyses of the line and its sublines indicated that both the IgM+ and IgA+ cells had identical c-myc and Ig JH gene rearrangements, indicating that they were derived from a common precursor, some of which eventually underwent an isotype switch. Ig VH gene sequence analyses of 21 molecular clones derived from the parental BRG BL line and two of its sublines demonstrated that all the clones used the same VH3 gene. Five unique intraclonal variants were identified at four distinct nucleotide positions (125, 161, 355, 375), which undoubtedly represented somatic mutations. Four of these five mutations occurred within complementary determining regions; all resulted in amino acid replacements. Moreover, an identical G to A nucleotide substitution that resulted in an identical amino acid change occurred at two distinct points in clonal evolution that were separated by the isotype class switch. Thus, the locations and types of the VH gene mutations, together with the occurrence of an isotype switch, are highly suggestive of an ongoing role for Ag stimulation and selection in the evolution of the malignant clone.

Adult↗
PubMed1984

Clonal evolution with isodicentric Ph1 chromosome in Ph1-positive CML: karyotypic conversion after bone marrow transplantation.

Clonal chromosomal evolution was observed in a 16-year-old boy suffering from Ph1-positive CML. An isodicentric Ph1 chromosome appeared 20 weeks after the initial diagnosis. At that time an allogeneic bone marrow transplantation was performed. Thereafter, during an observation period of more than 13 months, chromosome analyses showed neither the Ph1 chromosome nor the abnormal isodicentric variant. Close cytogenetic monitoring is suggested to reveal early unfavorable prognostic signs of the onset of blast crisis before it becomes evident in the bone marrow morphology.

Adolescent↗
PubMed1977

Cytogenetic evidence of clonal evolution in 5q- anemia.

The clinical homogeneity of myeloproliferative syndromes associated with a 5 q- marker can be contested, but nevertheless finds support in the 2 case reports we have cited. One of these observations of refractory anemia with partial myeloblastosis and 5 q- marker has shown a transformation into an acute myelomonocytic leukemia with clonal chromosomal evolution.

Aged↗
PubMed2006

Evidence for clonal evolution among highly polymorphic genes in methicillin-resistant Staphylococcus aureus.

The evolution of Staphylococcus aureus has been described as predominantly clonal, based on evidence from seven housekeeping genes. We aimed to test if this was also true for more polymorphic genes. In a collection of 60 isolates including major European epidemic methicillin-resistant S. aureus (MRSA) and sporadic MRSA strains, we compared the partial gene sequences of seven housekeeping genes (arcC, aroE, glpF, gmk, pta, tpi, and yqiL), six core adhesion genes (present in all strains) (clfA, clfB, fnbA, map, sdrC, and spa), and four accessory adhesion genes (not present in all strains) (ebpS, fnbB, sdrD, and sdrE). Nucleotide diversity of adhesion genes was 2- to 10-fold higher than genes used for multilocus sequence typing. All genes showed evidence for purifying selection with a weakly reduced level among accessory adhesion genes. Among these highly variable genes, there was no evidence for a difference in molecular evolution between epidemic and sporadic strains. Gene trees constructed from concatenated sequences of housekeeping, core adhesion, and accessory adhesion genes were highly congruent, indicating clonality, despite some evidence for homologous exchange. Further evidence for clonality was found with an overall positive correlation of allelic and nucleotidic divergence for both seven housekeeping genes and six core adhesion genes. However, for small allelic differences that fit the demarcations of clonal complexes (CCs) there was no such correlation, suggesting that recombination occurred. Therefore, despite an overall clonal population structure, recombination between related isolates within CCs might have contributed to S. aureus evolution.

Bacterial Proteins↗
PubMed2025

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.

NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.

Humans↗
PubMed2004

Evolution of clonal cytogenetic abnormalities in aplastic anemia.

Prior to the introduction of effective therapies, the high mortality rates of severe aplastic anemia (AA) precluded recognition of late complications of this disease. Once the survival of AA improved, observation of clonal evolution raised questions as to whether the development of secondary myelodysplastic syndrome (MDS) is a part of the extended natural history of the disease or is related to the therapies applied. Clinical features of myelodysplasia and AA can overlap, and typical MDS may evolve as a complication of AA. Common pathophysiologic elements operate in these diseases and are subject to many studies and theories as to what mechanisms in AA may lead to the late evolution of MDS. Similarly, AA has been hypothesized to be a reflection of an over-reactive immune response triggered by the appearance of genetically altered and/or phenotypically abnormal dysplastic clones. Hypocellular variants of myelodysplasia and responsiveness of certain forms of MDS to immunosuppressive regimens serve as the most appealing examples of the intricate and close pathophysiologic relationship of this disease with AA. The diagnosis of clonal evolution in the course of AA can be obvious if secondary cytopenia involves hypercellularity and a high percentage of blasts. In addition, the occurrence of a new karyotypic defect objectively heralds the progression of disease to MDS. However, the diagnostic imprecision of dysplasia recognition in the context of marrow hypocellularity, inability to obtain informative cytogenetics, and a high proportion of MDS cases with normal karyoptype have hampered studies designed to determine the frequency and timing of MDS evolution in AA. In addition, the diagnostic criteria and definitions used are not unified. While some centers recognize that the abnormal karyotype does not preclude the diagnosis of AA; in others, the diagnosis of AA includes the presence of normal karyoptype. Many typical features of dysplastic evolution in AA have been clarified. For example, karyotypes most frequently encountered in MDS secondary to AA involve chromosomes 6, 7 and 8. The evolution rates seem to be in the range of 10-15% in 10 years, but there are no predictive clues as to which patients are at greatest risk for this complication. Study of the mechanisms of clonal evolution in AA may help understand the pathophysiology of other forms of MDS and leukemia and also the mechanisms of antileukemic surveillance. Clinically, identification of patients at increased risk for clonal complications may influence the choice of therapies applied.

Anemia, Aplastic↗
PubMed1999

Transient leukemoid disorder in a newborn with Down syndrome followed 19 months later by an acute myeloid leukemia: demonstration of the same structural change in both instances with clonal evolution.

A transient leukemoid disorder (TLD) was observed in a newborn with Down syndrome (DS), demonstrating a clonal abnormality: 47,XX,der(X;15)(p10;q10),+21(c). Spontaneous remission was observed, but 19 months later an acute leukemia from the myeloid series was discovered. Cytogenetic study revealed the same structural change as at birth, with karyotypic evolution corresponding to addition of one chromosome 8 and a fourth chromosome 21. These findings demonstrate, at least in our patient, that TLD and the subsequent acute leukemia are closely related and that TLD, closely related to DS, must be viewed as a preleukemic disorder undergoing spontaneous remission. A review of literature data shows that most cytogenetic studies reported so far are related to either TLD or acute leukemia in DS. Serial studies performed in the same patient are quite infrequent and, to the best of our knowledge, there is only one other report demonstrating a cytogenetic relation between TLD and the subsequent acute leukemia.

Acute Disease↗