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Results for “Clonal Evolution”

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PubMed1997

Cytogenetic abnormalities and clonal evolution in an adult hepatoblastoma.

Hepatoblastomas usually occur in children < 3 years of age, and only occasional adult cases have been described. To date, 20 cytogenetically abnormal childhood hepatoblastomas have been reported. Karyotypic investigations have shown that most hepatoblastomas are diploid or hyperdiploid, often displaying trisomies for chromosomes 2 and 20. We have cytogenetically investigated an adult hepatoblastoma for which no previous karyotypic data exist. A hypertriploid stemline with multiple numerical and structural chromosomal aberrations, including +2 and +20, was found. In addition, the tumor displayed extensive clonal evolution with 11 subclones. Although the tumor thus displayed some chromosomal abnormalities commonly observed in childhood tumors, providing further support for the importance of these abnormalities in the development of hepatoblastoma, the level of genomic complexity seen in the present case has never been described in childhood hepatoblastomas and may suggest a different etiology or pathogenesis.

Aged↗

PubMed2002

Urothelial carcinoma of the renal pelvis with choriocarcinomatous features: genetic evidence of clonal evolution.

Urothelial carcinoma with choriocarcinomatous features is a rare malignancy arising in the urinary bladder or renal pelvis. We report the case of a 60-year-old man with a biphasic neoplasm of the right kidney composed of papillary urothelial carcinoma and choriocarcinoma. Widespread hepatic and pulmonary metastases with choriocarcinomatous features were found on autopsy 6 weeks after initial diagnosis. Chromosomal analysis revealed a close genetic relationship between the papillary urothelial and choriocarcinomatous tumor components, documenting for the first time that choriocarcinoma of the renal pelvis results from clonal evolution of urothelial carcinoma with acquisition of trophoblastic differentiation.

Carcinoma, Transitional Cell↗

PubMed1986

Cytogenetic evidence for clonal evolution in B-cell chronic lymphocytic leukemia.

Sequential cytogenetic studies were performed in eight of ten patients with B-cell chronic lymphocytic leukemia presenting with trisomy 12 as the sole chromosomal abnormality. Follow-up studies of peripheral blood lymphocytes revealed that the karyotypes retained the sole abnormality of trisomy 12 in five cases, trisomy 12 converted to a normal karyotype during remission in one case, additional chromosome changes (-X,14q-) along with trisomy 12 appeared in one patient and multiple chromosome changes with or without trisomy 12 appeared in the remaining patient. The findings indicate that other chromosome changes in addition to trisomy 12 may develop as a result of clonal evolution or dedifferentiation, though the possibility that in two patients these changes may be related to chemotherapy and/or irradiation could not be ruled out entirely.

Aged↗

PubMed1986

Chromosomal study demonstrating the clonal evolution and metastatic origin of a metachronous colorectal carcinoma.

Detailed cytogenetic studies were performed on 3 samples of a metachronous rectal carcinoma. Two samples were obtained from the primary tumor, and one from a secondary growth which arose 10 months after surgical removal of the primary. All 149 R-banded metaphases analysed were abnormal and most likely derived from the same modified karyotype: 45, XY, -1, -18, +20 der(6) t(1;6) (q21.100;q22.3), i(17q). These data are consistent with our previous findings that the loss of chromosome 18 and of the short arm of chromosome 17 may be the primary chromosomal changes associated with carcinoma of the large bowel. From all the karyotypes observed, a typical clonal evolution could be reconstructed, indicating that the second tumor was indeed metastatic from the first one, based on similar chromosome markers. An identical secondary chromosomal anomaly, i.e. gain of chromosome 8 or X, occurred independently twice in two different cell populations during the evolution of this tumor.

Carcinoma↗

PubMed1993

Chromosomal biomarkers in the clonal evolution of head and neck squamous neoplasia.

The biological behavior of any tumor is the result of changes in gene expression caused by mutations accumulated in the carcinogenic process. In squamous carcinoma of the head and neck (SCCHN) there are numerous complex chromosome abnormalities. To make sense of this complexity it is necessary to identify the consistent chromosome changes in a large panel of tumors, to determine if these changes are true representations of the in vivo situation, and to construct a map of gene loci likely to be involved in the development and progression of cancer. Our findings indicate that cultured tumor cells are cytogenetically stable when compared to cells evolving in vivo. We also found that clues to the sequence of events in clonal evolution of individual tumors can be deduced by studying primary and metastatic tumors from the same patient, by examining separate clones within the same tumor, and by analyzing ploidy changes. Furthermore, comparison of the in vitro karyotypes to in situ analysis of the tumor tissue indicates that in vitro cultures are good representations of the in vivo tumor. We conclude that identification of consistent chromosome changes in cultured cells can lead to the loci of genes important in the clinical behavior of individual tumors. The most frequent chromosome abnormalities in SCCHN, found in 40-60% of tumors, are deletions affecting 3p, 5q, 8p, 9p, and 18q. Less common consistent changes found in 30-40% of tumors are gains affecting 3q, 5p, 7p, 8q, and 11q. Preliminary evidence suggests that loss of 18q may be prognostically important and may involve disruption of genes encoding cell adhesion molecules.

Carcinoma, Squamous Cell↗

PubMed1978

Clonal evolution in atypical chronic granulocytic leukemia: a non-Philadelphia translocation.

Hemopoietic cells in chronic granulocytic leukemia (CGL) frequently contain a chromosome translocation involving chromosome 22 and another autosome, usually number 9. The translocated chromosome 22 is known as the Philadelphia (Ph) chromosome. The appearance of a second Ph chromosome is the most common cytogenetic abnormality in CGL signaling the blastic phase. For 6 yr we serially studied a man with atypical CGL whose marrow cells were marked by a translocation from chromosome 18 to chromosome 11 [46XY,t(11;18)(q23;q12)]. Three months prior to blast transformation there appeared an extra copy of the marker chromosome 18: 47XY,t(11;18)(q23;q12),+(18p11 leads to 18q12). This man presents a new cytogenetic pattern of clonal evolution in CGL. The pattern is analogous to that of the Ph chromosome and is characterized by a balanced chromosomal rearrangement and the subsequent acquisition of an extra copy of the small translocation chromosome immediately prior to blast transformation.

Adult↗

PubMed2000

Apparently unrelated clones shown by spectral karyotyping to represent clonal evolution of cryptic t(10;11)(p13;q23) in a patient with acute monoblastic leukemia.

The accurate genetic classification of acute leukemia is of the utmost clinical importance for treatment stratification. In the present study, we report on a young girl with aggressive acute monoblastic leukemia (AML) (M5b) with skin, lymph node, and bone marrow involvement, in whom cytogenetic analysis revealed three clones with different secondary chromosomal changes. Two clones had the secondary +8 and del(9q) aberrations, with the der(11)t(1;11) in the second one; the third clone was apparently unrelated to the others, and had add(7)(p?21),-13,+22. Using the spectral karyotyping (SKY) technique, we found that all three clones originated from a common clone that harbored the hidden primary t(10;11)(p13;q23) or its derivatives, suggesting clonal evolution. The first clone had the balanced t(10;11), the second had its derivative, der(10)t(10;11), and the third had the other derivative, der(11)t(10;11). On fluorescence in situ hybridization (FISH), MLL gene splitting, with translocation of its centromeric portion to 10p, and deletion of its telomeric portion, was demonstrated. In conclusion, the detection of the very poor prognostic t(10;11) aberration in AML, was possible by complementing the traditional cytogenetic analysis with SKY and FISH.

Bone Marrow Cells↗

PubMed2000

Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution.

A remarkable instability at simple repeated sequences characterizes gastrointestinal cancer of the microsatellite mutator phenotype (MMP). Mutations in the DNA mismatch repair gene family underlie the MMP, a landmark for hereditary nonpolyposis colorectal cancer. These tumors define a distinctive pathway for carcinogenesis because they display a particular spectrum of mutated cancer genes containing target repeats for mismatch repair deficiency. One such gene is BAX, a proapoptotic member of the Bcl-2 family of proteins, which plays a key role in programmed cell death. More than half of colon and gastric cancers of the MMP contain BAX frameshifts in a (G)(8) mononucleotide tract. However, the functional significance of these mutations in tumor progression has not been established. Here we show that inactivation of the wild-type BAX allele by de novo frameshift mutations confers a strong advantage during tumor clonal evolution. Tumor subclones with only mutant alleles frequently appeared after inoculation into nude mice of single-cell clones of colon tumor cell lines with normal alleles. In contrast, no clones of BAX-expressing cells were found after inoculation of homozygous cell clones without wild-type BAX. These results support the interpretation that BAX inactivation contributes to tumor progression by providing a survival advantage. In this context, survival analyses show that BAX mutations are indicators of poor prognosis for both colon and gastric cancer of the MMP.

Animals↗

PubMed1982

The isochromosome (17q) in chronic myelocytic leukaemia: mechanism of origin, centromeric function and clonal evolution.

An isochromosome (17q) may be observed in myelo- and lymphoproliferative disorders, as well as in solid tumours and it is very frequent in Ph1-positive chronic myelocytic leukaemia (CML) during the blastic phase. A study on the mechanism of origin and on the centromeric function of the i(17q)s was performed by means of the C- and Cd-staining techniques in four CML patients. In all these cases, as well as in four others reported in the literature, the i(17q) is dicentric thus indicating that its origin is due to a break on the short arms followed by joining of the two chromatids containing the centromere. The Cd-technique indicates that one of the two centromeres is inactive: this result is consistent with the fact that the i(17q) in CML is a step in the clonal evolution towards the acute phase.

Adolescent↗

PubMed2005

Clonal evolution of stem and differentiated cells can be predicted by integrating cell-intrinsic and -extrinsic parameters.

Stem cells and their derivatives represent a renewable source of cells for therapeutic applications. However, the inability to quantitatively integrate and exploit the effects of multiple parameters on the fate of stem cells limits their use in clinical applications. To address this, we developed a computational model that combines probabilistic, individual-cell and deterministic cell-population parameters to simultaneously calculate the specific effects of exogenous and endogenous factors on the overall population-dynamics behaviour. The model tracks the progeny trajectory of individual cells over several generations as a threshold function of ligand-receptor signalling interactions. Simulations in silico were validated against an Oct 4-promoter-driven green-fluorescent-protein-expressing murine embryonic stem cell line, and used to understand the effects of key parameters on the clonal evolution of stem versus differentiated cells in this system. Our approach demonstrated the ability to distinguish between individual-cell and population-averaged parameters with respect to their effects on governing dynamic behaviour. Moreover, we could discriminate between digital versus graded regulation of the Oct 4 transcription factor in accounting for experimental observations. Finally, we showed that our approach could be generalized to other stem-cell systems, in particular the previously characterized intestinal crypt system, in elucidating relative contributions of stem and progenitor cells to population output. On the basis of all these results, we believe that our iterative experimental and computational approach has been found to be useful for the study of various stem-cell systems.

Animals↗

PubMed2002

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases.

VIN is thought to be the precursor of some VSCCs because it is monoclonal, frequently occurs contiguously with VSCC and shares similar risk factors with a subgroup of VSCC. There has been no conclusive molecular evidence supporting this assumption. We performed X-chromosome inactivation analysis on 9 cases of lone VIN, 10 cases of VSCC and associated contiguous VIN and 11 cases of VSCC and associated noncontiguous VIN. Eight of the 9 cases of lone VIN appeared to be monoclonal. All 7 informative and monoclonal cases of VIN with contiguous VSCC and 6/9 informative cases of VIN with noncontiguous VSCC showed patterns of X-chromosome inactivation consistent with a common monoclonal origin for both VIN and VSCC. Two of the 9 cases of VIN with noncontiguous VSCC showed X-chromosome inactivation patterns consistent with a separate clonal origin. We performed LOH analysis at 6 chromosomal loci on these samples and 7 cases with lymph node metastases. Identical losses occurred 7 times in VIN and contiguous VSCC (random probability 1.2 x 10(-9)), twice in VIN and noncontiguous VSCC (random probability 1.5 x 10(-3)) and 3 times in VSCC and associated metastases (random probability 1.8 x 10(-5)). Some losses occurring in VSCC did not appear in the contiguous VIN or associated metastases and vice versa. These data provide molecular evidence that VIN is the precursor of VIN-associated VSCC, that multifocal disease may arise via either different clones or a single clone and that continued divergent clonal evolution may occur in vulval neoplasia.

Carcinoma, Squamous Cell↗

PubMed2004

Predominant clonal evolution leads to a close parity between gene expression profiles and subspecific phylogeny in Trypanosoma cruzi.

We investigated the relationships between overall phylogenetic diversity in Trypanosoma cruzi evidenced by multilocus markers (MLEE and RAPD) on the one hand, and gene expression patterns, revealed by mRNA analysis on the other hand. Nineteen laboratory-cloned stocks representative of this parasite's overall phylogenetic diversity and ecogeographical range were analyzed using random amplified differentially expressed sequences (RADES). The bat trypanosome T. cruzi marinkellei was taken as outgroup. The profiles obtained showed that RADES polymorphism cannot be considered as a simple subsample of general RAPD polymorphism. Indeed, many RADES bands were not present in general RAPD profiles, and vice versa. Phylogenies obtained from RADES on the one hand, and MLEE/RAPD on the other hand, were very similar. This suggests that in spite of the recent observation of hybrid genotypes and mosaic genes in T. cruzi, clonal evolution in this parasite has been preponderant enough on an evolutionary scale to carve the polymorphism on all types of DNA sequences, including expressed genes, although these genes are assumed to undergo natural selection pressure contrary to noncoding sequences and neutral polymorphisms.

Animals↗

PubMed2002

Karyotypic heterogeneity and clonal evolution in squamous cell carcinomas of the head and neck.

Head and neck squamous cell carcinomas (HNSCC) are often characterized by complex karyotypic changes, and a substantial proportion of the reported tumors have shown intratumor heterogeneity in the form of cytogenetically related (40%) or unrelated clones (20%). In order to study intratumor heterogeneity and to distinguish the temporal order of chromosome rearrangements in these tumors, two or more samples from different areas of the same tumor were separately examined in 19 HNSCC, yielding karyotypes from a total of 42 tumor samples. Intrasample heterogeneity was observed in 16 samples. Two samples displayed both related and unrelated multiple clones, four samples showed only multiple unrelated clones, and the remaining 10 samples had only related subclones. Intersample heterogeneity was detected in all but one tumor. Five tumors showed both cytogenetically related and unrelated multiple clones, 11 were found to have only related subclones, and the remaining two tumors showed only unrelated clones. Clonal evolution could be assessed in 13 tumors. A comparison of chromosome imbalances in different subclones from these tumors suggests that partial or entire loss of 3p, 8p, 9p, and 18q and gain of genetic material from 3q and 8q are likely to be early genetic events. In contrast, loss of 1q, 6p, 7q, and chromosome 10, as well as gain of chromosome arms 5p and 7p, are most probably later genetic events. One of the examined tumors contained two highly complex clones that were cytogenetically unrelated, indicating that this tumor had a multicellular origin.

Adult↗

PubMed2006

IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia.

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).

Aged↗

PubMed2002

Clonal evolution of blasts in an elderly patient with CD56(+) relapsed acute promyelocytic leukemia.

We describe an elderly patient with acute promyelocytic leukemia (APL), whose leukemic cells expressed CD56 antigen at relapse but not at diagnosis. Chromosome analysis revealed that blasts with t(8;15;17)(q24.1;q22;q11.2) increased from 4 of 20 cells (20%) at first relapse to 10 of 14 cells (71.4%) at second relapse. In addition, the positivity for CD56 expression on blasts judged by flow cytometric analysis using CD45 blast gating was also increased from 14.2% at first relapse to 75% at second relapse. Although conventional chemotherapy was performed for the initial disease and the first relapse, relapse developed again. Therefore, three courses of intensive postremission chemotherapy including concurrent administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) with cytarabine were performed after achievement of complete remission (CR) by the treatment with all-trans-retinoic acid (ATRA). Although PML-RARalpha mRNA was not detectable by reverse transcription polymerase chain reaction (RT-PCR), a third relapse occurred. This case demonstrated clonal evolution from a CD56(-) to a CD56(+) blast population and provided further support for the suggestion that CD56 expression might be an unfavorable prognostic factor in t(15;17) APL.

Aged↗

PubMed1993

Analysis of rearranged immunoglobulin genes indicating a process of clonal evolution in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is known to be a stable monoclonal neoplasm. In contrast to early studies demonstrating no more than two hybridizing immunoglobulin heavy chain bands corresponding to the two expected alleles, we have demonstrated an unexpected multiband pattern when the HindIII-digested DNA samples from 38 CLL patients were analysed by Southern blot hybridization using JH and C mu gene probes. In order to characterize the genetic basis for the multiband pattern, we molecularly cloned the immunoglobulin heavy chain genes of one of the patients whose leukaemic DNA sample demonstrated three hybridizing JH bands and a loss of the germline band. The cloned rearranged immunoglobulin genes could be divided, based on the restriction mapping and the hybridization with the various probes, into two basic patterns representing two alleles. In one of the cloned rearranged immunoglobulin genes a secondary rearrangement occurred that resulted in the addition of 300 base-pair long sequence into the switch region, and the creation of a HindIII restriction site. The results of the study suggest that clonal evolution occurs in some CLL, and that many of these neoplasms are indeed oligoclonal due to the accumulation of secondary genetic changes.

Antibodies, Neoplasm↗

PubMed2006

Chronic myeloproliferative diseases with the t(5;12)(q33;p13): clonal evolution is associated with blast crisis.

Chronic myeloproliferative diseases (CMPDs) associated with t(5;12)(q33;p13) are reported to be responsive to imatinib mesylate. We studied 5 cases of CMPD with isolated t(5;12) treated at our hospital between January 1993 and October 2004. All were men with a median age of 55 years (range, 18-68 years). In the peripheral blood, each had marked leukocytosis, with variable eosinophilia (n = 4), monocytosis (n = 3), or basophilia (n = 2). Bone marrow specimens were hypercellular (70%-100%) with marked myeloid hyperplasia in each patient, but only 1 patient had eosinophilia, monocytosis, and basophilia. Follow-up ranged from 23 to 182 months (median, 48 months). Four died 23 to 182 months after initial diagnosis, 3 of blast crisis and 1 of cardiac complications of severe eosinophilia. Additional cytogenetic aberrations were identified at the time of blast crisis. Of 3 patients treated with imatinib, 2 responded, but only 1 had a sustained response. CMPD with t(5;12) commonly transforms to blast phase, and transformation is associated with cytogenetic evidence of clonal evolution.

Adolescent↗

PubMed2003

Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area.

Deciphering the structure of pathogen populations is instrumental for the understanding of the epidemiology and history of infectious diseases and for their control. Although Mycobacterium tuberculosis is the most widespread infectious agent in humans, its actual population structure has remained hypothetical until now because: (i) its structural genes are poorly polymorphic; (ii) adequate samples and appropriate statistics for population genetic analysis have not been considered. To investigate this structure, we analysed the statistical associations (linkage disequilibrium) between 12 independent M. tuberculosis minisatellite-like loci by high-throughput genotyping within a model population of 209 isolates representative of the genetic diversity in an area with a very high incidence of tuberculosis. These loci contain variable number tandem repeats (VNTRs) of genetic elements named mycobacterial interspersed repetitive units (MIRUs). Highly significant linkage disequilibrium was detected among the MIRU-VNTR loci in this model. This linkage disequilibrium was also evident when the MIRU-VNTR types were compared with the IS6110 restriction fragment length polymorphism types. These results support a predominant clonal evolution of M. tuberculosis.

Bacterial Typing Techniques↗