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Results for “Clonal Evolution”

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PubMed1991

Biclonal analysis of busulfan-induced sister chromatid exchange in blast crisis of Philadelphia chromosome-positive chronic myeloid leukemia.

The frequency of induced sister chromatid exchange (SCE) as a sensitive parameter for chemotherapy resistance was studied after in vitro treatment with busulfan in four cases of myeloid blast crisis of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Prerequisite was a chromosomally biclonal condition with cells characterized by numerical and/or structural clonal evolution [e.g., +8, +17, +19, or i(17q)] and those only Ph+, which allowed a direct comparison of both clones. We found almost identical mean SCE frequencies in cells with and without clonal evolution after in vitro treatment with 1, 3, and 5 micrograms busulfan. The distribution of the SCE frequency within chromosome groups also remained similar in all cases. Because the SCE assay has proven a very sensitive tool for detection of resistance to chemotherapy with alkylating agents, we conclude that the clonal evolution of CML blast crisis is not associated with a significant degree of chemotherapy resistance. Other aspects, e.g., the lack of normal bone marrow cells necessary for reconstitution of hematopoiesis, may play a more important role in the poor results of chemotherapy in myeloid CML blast crisis.

Blast Crisis↗

PubMed1993

Composite lymphoma and related disorders.

Lymphomas evolve over time, usually from the small-cell to the large-cell category, and from follicular histologic characteristics to diffuse architecture. The histologic characteristics of lymphomas may be discordant in patients with multiple sites of involvement. When different types of lymphomas are encountered in a single organ or tissue, they are designated as CLs in the Working Formulation of NHL. The most common CLs consist of different subsets of follicular center cell lymphomas, usually one with low-grade follicular histologic characteristics and another with diffuse architecture and/or more aggressive cytologic features. These lymphomas now are considered to represent different phases of clonal evolution rather than representing a coincidental simultaneous occurrence of two unrelated lymphomas. Whether B-cell large-cell lymphoma coexisting with another B-cell lymphoma, namely, the nodular variant of lymphocyte-predominant Hodgkin's disease, also represents clonal evolution requires further study. Composite lymphomas consisting of a B-cell lymphoma and a T-cell lymphoma are extremely rare. The histogenetic implications for a clonal relationship between component subsets in these and other equally rare combinations remain uncertain. The CLs should continue to be recognized because (1) the component morphologic subsets may have entirely different natural histories, requiring different treatment modalities although they may be clonally related; and (2) the study of such cases may provide us with information regarding the complex interrelationship of the lymphoid system and its clonal evolution. The morphologic definition for CL of the Working Formulation should continue to be used whenever possible, with addition of appropriate immunologic and/or molecular-genetic data.

Hodgkin Disease↗

PubMed1992

Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of interferon-alpha (IFN-A) and low-dose cytarabine (ara-C) combination chemotherapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Sixty patients with advanced phases of Philadelphia chromosome (Ph)-positive CML received combination therapy with IFN-A 5 x 10(6) U/m2 daily, and low-dose ara-C 15 mg/m2 daily for 2 weeks every 4 weeks until remission, then for 1 week every month as maintenance. Forty patients were in late chronic-phase CML, and 20 were in accelerated-phase CML (16 with clonal evolution only, four with other criteria). Their outcome was compared with 58 patients (39 late chronic-phase CML and 19 accelerated-phase CML) who had been previously treated with IFN-A alone in the same dose schedule. RESULTS: In late chronic-phase CML, patients receiving IFN-A plus ara-C had a better complete hematologic response (CHR) rate compared with those treated with IFN-A alone (55% v 28%; P = .02), a trend for better Ph suppression (15% v 5%; P = .13), and a longer survival (3-year survival rate 75% v 48%; P less than .01). These differences do not seem to be caused by imbalances in prognostic factors between the two treatment groups. In accelerated-phase CML, the addition of ara-C to IFN-A did not improve the response rate of treated patients, and the difference in survival was accounted for by different patient characteristics. Suppression of clonal evolution was observed in five patients (25%). Patients with clonal evolution as the only criterion for disease acceleration had a longer survival than those with other or additional accelerated-phase criteria (3-year survival rate 67% v 22%; P less than .01). CONCLUSION: The results with the combination of IFN-A plus ara-C in late chronic-phase CML are encouraging, and suggest the need for its evaluation in early chronic-phase CML.

Adult↗

PubMed1997

Cytogenetics of chronic myelogenous leukaemia.

The Philadelphia (Ph) chromosome is present in the leukaemic cells of most patients with chronic myelogenous leukaemia. Variant translocations occur in 10% of patients but breakpoints on chromosomes 9 and 22 remain the same, so prognosis of these patients is unchanged. Clonal evolution is infrequent in chronic phase and its significance depends on the specific chromosome involved, the number of metaphases affected and the timing in the chronic phase. The majority of patients in blastic phase demonstrate clonal evolution; three specific abnormalities (+Ph, +8 and isochromosome 17q) are present in 70% of patients. Loss of the Ph chromosome on therapy is associated with prolonged survival. For monitoring these events conventional G-band cytogenetics (CG) is essential at presentation to characterize the Disease cytogenetically, while fluorescence in situ hybridization (FISH) on hypermetaphase preparations (hypermetaphase FISH (HMF)) is important for establishing the specific frequency of Ph+ cells. During treatment FISH on interphase cells (I-FISH) can monitor the level of Ph+ cells in circulation, while CG may be used to identify any suspected clonal evolution. Where I-FISH is negative, HMF is essential to evaluate minimal residual disease.

Chromosomes, Human, Pair 12↗

PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗

PubMed1994

A polymerase chain reaction study of the stability of Ig heavy-chain and T-cell receptor delta gene rearrangements between presentation and relapse of childhood B-lineage acute lymphoblastic leukemia.

Ig heavy-chain (IgH) and partial V delta 2-D delta 3 T-cell receptor (TCR) gene rearrangements were investigated, by polymerase chain reaction (PCR) amplification and sequence analysis, in 52 patients at presentation and first relapse and in 14 at both first and second relapse of B-lineage acute lymphoblastic leukemia. In combination, these techniques amplified one or more clonal markers at presentation in 90% of patients (IgH-PCR, 75%; V delta 2-D delta 3-PCR, 46%; both, 33%). Changes in the pattern of amplification between presentation and first relapse were seen in 31% of patients positive by IgH-PCR at presentation and in 25% of those positive by TCR delta-PCR. Only 3 patients showed complete change in their rearrangements, which is suggestive of relapse with a new clone. Furthermore, despite the high reported rates of oligoclonality and clonal evolution at the IgH locus, the results presented show that false-negative minimal residual disease (MRD) detection can be avoided by designing D-N-J probes to all presentation rearrangements. Using a PCR approach for both gene markers, false-negative testing because of clonal evolution would have only occurred in 3 (8%) of the IgH-positive patients, in contrast to 5 (21%) of V delta 2-D delta 3-positive patients. Combining these two systems increases the proportion of patients open to study to 90%, allows comparative studies of the sensitive of the two methods, and reduces the rate of false-negative assessment of MRD caused by clonal evolution to less than 10%. We conclude that large prospective PCR studies of MRD detection should examine gene rearrangements at multiple loci to maximize their applicability and to minimize false-negative relapse prediction.

Adolescent↗

PubMed2004

Enhanced stem cell survival in familial adenomatous polyposis.

Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.

Adenomatous Polyposis Coli↗

PubMed1989

Cytogenetic studies of 21 patients with acute lymphoblastic leukemia in relapse.

Karyotypes of 21 patients, originally entered into the Third International Workshop on Chromosomes in Leukemia (3IWCL), were investigated in first, second and/or subsequent relapses. Karyotypes at diagnosis were related to the relapses in the following ways: normal to normal (N-N) (five cases); abnormal to normal (A-N) (two cases); abnormal to abnormal with no change (A-A) (five cases); abnormal to abnormal with clonal evolution (A-A+) (eight cases); and normal to abnormal (N-A) (one case). The A-A group comprised two each of t(4;11) and t(9;22) cases and one pseudodiploid case; included in this group were the only two patients who did not receive intensive treatment. Both A-N cases had been pseudodiploid at diagnosis. Clonal evolution A-A+ occurred in patients who had had 47-49 chromosomes or pseudodiploidy at diagnosis and was mainly due to the addition of structural change. The additional abnormalities were different in each case. The only de novo appearance of a clone (N-A) was in host cells in relapse following bone marrow transplantation. Clonal evolution occurred in patients who had been intensively treated and who relapsed late; the median time from diagnosis to relapse studied for the A-A group was 6 months and for the A-A+ group was 24 months. Survival following relapse was shorter for patients who had had a clonal abnormality at any time (median 10 months) than for those with no abnormality at diagnosis or in relapse (median 26 months).

Adolescent↗

PubMed2005

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy.

Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pretherapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinibnaive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 patients with chronic myelogenous leukemia (CML), using cDNA sequencing and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing, and 1 by sequencing only (overall frequency, 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 patients with positive ASO-PCR had follow-up samples available for sequencing. Wild-type sequence was detected in 6 of 11, 2 different mutations in 1 of 11, and identical mutations in 4 of 11 patients, 2 of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine, and a low platelet count, but not with response to imatinib, event-free survival, and overall survival. KD mutants present at low levels do not invariably lead to relapse, and additional factors are required to induce a fully drug-resistant phenotype.

Adult↗

PubMed1987

Cytogenetics and cell surface marker analysis in chronic myelocytic leukemia. II. Implications for patient management.

Chronic myelocytic leukemia (CML) is a model system for the study of many aspects of malignant disease. One aspect that correlates with decreasing therapeutic response is tumor progression. This progression is often accompanied by clonal evolution. In those cases where aggressive therapy does not prevent this evolution, the clinical response to therapy usually proves to be poor and of short duration. Investigators are concentrating their efforts in three primary, but not mutually exclusive, areas with respect to the clinical management of CML. These include: an attempt to distinguish patients at risk for early transformation from those who will have a prolonged chronic phase; the cryopreservation of autologous bone marrow or buffy coat early in chronic phase for subsequent use in the accelerated phase and; endeavors to identify early markers for disease progression allowing intervention before an irreversible blast crisis occurs. This report deals with two types of potential prognostic markers of transformation: chromosomal and cell surface characteristics. The appearance of nonrandom abnormal chromosomal patterns has been correlated with myeloblastic transformation by many investigators. However, there has always been a subset of CML patients who do not undergo clonal evolution. Additionally, the type(s) of transformation in CML may vary depending on the cell lineages involved. Unlike myeloblastic transformants, many of our patients who do not exhibit clonal evolution as a concomitance of disease progression develop a lymphoblastic transformation. Cytofluorometric analysis can distinguish small populations of abnormal cells with lymphoblastic characteristics (HLA DR+). Initial data suggests that patients expressing the HLA DR+ in their "normal" peripheral blood cells are at risk of undergoing lymphoblastic transformation. The combined use of clinical, cytogenetic, and cytofluorometric data to predict an impending transformation and to discriminate between myeloblastic and lymphoblastic populations allows clinicians to manage their patients more effectively.

Adolescent↗

PubMed2006

Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines.

The processes mediating genomic instability and clonal evolution are obscure in multiple myeloma (MM). Acquisition of new chromosomal translocations into the switch region of the immunoglobulin heavy chain (IgH) gene (chromosome 14q32) in MM, often heralds transformation to more aggressive disease. Since the combined effects of CD40 plus interleukin-4 (IL-4) mediate IgH isotype class switch recombination (CSR), and this process involves DNA double strand break repair (DSBR), we hypothesized that CD40 and/or IL-4 activation of MM cells could induce abnormal DNA DSBR and lead to genomic instability and clonal evolution. In this study, we show that MM cell lines that are optimally triggered via CD40 and/or IL-4 demonstrate abnormal decoupling of IL-4 signal transduction from CD40. Specifically, CD40 alone was sufficient to trigger maximal growth of tumor cells. We further demonstrate that CD40 triggering induced both DNA DSBs as well as newly acquired karyotypic abnormalities in MM cell lines. Importantly, these observations were accompanied by induction of activation induced cytidine deaminase expression, but not gross apoptosis. These data support the role of abnormal CD40 signal transduction in mediating genomic instability, suggesting a role for the CD40 pathway and intermediates in myelomagenesis and clonal evolution in vivo.

CD40 Antigens↗

PubMed1993

Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction.

We sequentially studied bone marrow (BM) samples of 25 patients in complete remission of an acute lymphoblastic leukemia (ALL) using a simplified polymerase chain reaction (PCR) strategy (direct use of the PCR product as a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a first approach. BM aspirates were serially investigated after obtention of a complete response. When sensitivity was less than 1:10(4), the PCR fragment was sequenced and a specific oligonucleotide was synthetized and used as a probe (five cases). Cases in which minimal residual disease (MRD) became undetectable were cross-controlled using either TCR delta rearrangement or a specific translocation to circumvent the problem of false-negative results arising from clonal evolution. The median follow-up was 30 months (3 to 51 months). Within the first 3 months of complete remission, MRD was detectable in 22 of 23 investigated patients and remained so in 19 of 21 patients examined at 6 months, regardless of the long-term clinical outcome. In patients remaining in complete remission at 30 months or more, two patterns of MRD emerged during the follow-up. Either it continuously decreased to ultimately become undetectable (five patients) or remained detectable (five patients) with an increase after discontinuation of treatment in two. In the eight patients who relapsed, MRD persisted throughout the clinical course, and eventually increased 3 to 12 months before relapse was clinically detectable. In one case, clonal evolution of the VDJ heavy chain region was observed and recurrence of MRD shown by the use of TCR delta rearrangement as a control. We conclude that the use of this simplified methodology is a valuable tool for the follow-up of MRD in a majority of ALL patients, though in a few cases, sequencing needs to be performed to achieve a relevant sensitivity. The possibility of clonal evolution requires a cross-control of any sample becoming negative whatever the initial rearrangement used to generate a probe. In patients on therapy, sequential search for MRD seems to be a good tool for predicting the long-term outcome. In addition, patients remaining positive at the time treatment is discontinued or with a high tumor burden after a few months therapy may be at a higher risk of subsequent relapse, although a longer follow-up is needed to answer this question.

Adolescent↗

PubMed2006

Imatinib resistant chronic myelogenous leukemia, BCR-ABL positive by chromosome and FISH analyses but negative by PCR, in a child progressing to acute basophilic leukemia: cytogenetic follow-up.

The case of an 11-year-old child with adult-type chronic myeloid leukemia, Philadelphia (BCR-ABL) positive, reverse transcription-polymerase chain reaction negative for the major, minor, and micro breakpoints is presented. In the course of 3 years, the child failed to respond to treatment with hydroxyurea, refused all therapy for 6 months, was intolerant to alpha-interferon and progressed, while on imatinib, to acute basophilic leukemia. Subsequently he underwent successful bone marrow transplantation. A secondary cytogenetic clonal evolution, i(17q), developed during hydroxyurea treatment and a tertiary clonal evolution, +8, was detected during imatinib treatment. It is not clear to what extent the several factors (undefined BCR-ABL breakpoint, treatment avoidance, and initial treatment choices, alone or in combination) played a role in the imatinib relapse and resistance and in the disease progression. We conclude that close follow-up with frequent bone marrow sampling is crucial in order to monitor such patients for early relapse and prompt referral for bone marrow transplant.

Antineoplastic Agents↗

PubMed2003

The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment.

PURPOSE: Imatinib mesylate is a tyrosine kinase inhibitor with high affinity for the BCR-ABL fusion protein expressed by the hematopoietic cells in chronic myelogenous leukemia (CML). Some patients with chronic-phase or accelerated-phase CML either relapse after an initial response or are refractory to imatinib, prompting us to evaluate the efficacy of dose increase in such patients. EXPERIMENTAL DESIGN: Twelve chronic-phase patients initially receiving 400 mg/day and 4 patients with accelerated phase initially receiving either 400 mg/day (two patients) or 600 mg/day (two patients) had their dose increased (14 to 800 mg/day and 2 to 600 mg/day) because of progressive disease (usually clonal evolution) or inadequate cytogenetic response after at least 1 year of therapy. RESULTS: Six patients had major cytogenetic responses after dose increase (3 complete and 3 partial). Two others had minor cytogenetic responses. Two patients with clonal evolution transiently lost the additional clonal aberrations. Almost all of the responses occurred within 6 months, and were typically 3-6 months in duration. However, 3 patients have continuing major cytogenetic responses of >18 months duration. Dose increase was well tolerated, with thrombocytopenia, mild leukopenia, and exacerbation of prior edema being the most common adverse events. CONCLUSIONS: Although increasing the dose of imatinib can benefit a subgroup of patients with CML with either an inadequate cytogenetic response or disease progression, our results suggest the majority will not have a sustained meaningful response, and that other options, such as allogeneic stem cell transplant or investigational therapies, also need to be considered at the time of dose increase.

Adult↗

PubMed2004

Clonal cytogenetic abnormalities in Philadelphia chromosome negative cells in chronic myeloid leukemia patients treated with imatinib.

Treatment of chronic myeloid leukemia (CML) with imatinib (Gleevec) induces a much higher rate of partial and complete cytogenetic responses (CCR) than interferon-alpha (IFN)-based therapies. Conventional wisdom suggests that elimination of the Philadelphia (Ph)- positive cells will lead to re-establishment of normal Ph-negative hematopoiesis. Surprisingly, karyotypic abnormalities were detected in the chromosome negative cells of some patients with cytogenetic response to imatinib. In some cases, this was associated with a myelodysplastic syndrome (MDS). While clonal evolution in Ph-positive cells is considered part of the progression of CML, clonal evolution in Ph-negative cells had been observed only rarely in a small number of patients treated with IFN or bone marrow transplantation, raising the question whether the phenomenon may be causally linked to imatinib therapy. In this manuscript, we will review the currently available data, suggest possible causes and discuss potential implications for patient management. We are fully aware that a systematic study of a larger patient cohort will be required to conclusively address these issues.

Benzamides↗

PubMed1998

Cytogenetic analysis of de novo acute myeloid leukemia with trilineage myelodysplasia in comparison with myelodysplastic syndrome evolving to acute myeloid leukemia.

Characteristics of karyotypes were analyzed in de novo acute myeloid leukemia (AML) with trilineage myelodysplasia (AML/TMDS) at initial diagnosis and compared with myelodysplastic syndrome (MDS) cases that had evolved to AML (MDS/AML). Abnormal karyotypes were seen in 11 of 19 patients with AML/TMDS and 13 of 16 MDS/AML cases. Trisomy 8 was observed in 3 AML/TMDS cases as a sole anomaly and was also present in 3 MDS/AML cases but not as a sole finding. Although MDS/AML frequently displayed monosomies or long-arm deletions of chromosome 5, 7 and 9, only one case exhibited long-arm deletion (of chromosome 7) in AML/TMDS. Two or more chromosome aberrations were found in some cases in both groups. These findings suggest that AML/TMDS had passed through several preleukemic stages at diagnosis, as has been well documented in MDS and MDS/AML. Additionally, clonal evolution may have already occurred in AML/TMDS, as MDS transformed to AML is associated with clonal evolution.

Acute Disease↗

PubMed1994

Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors.

Chromosome studies of lipomas have revealed an extensive cytogenetic heterogeneity. To investigate the frequencies of previously recognized cytogenetic subgroups and to find out if more recurrent rearrangements can be identified, we have analyzed cytogenetically short-term tissue cultures of 237 samples from 188 adipose tissue tumors obtained from 142 patients. Only one of 58 tumors from 18 patients with multiple lipomas (more than two tumors) had karyotypic changes. Among the sporadic lipomas, 20 tumors had supernumerary ring chromosomes of unknown origin, 55 had different aberrations involving chromosome segment 12q13-15, 11 had changes of 6p or chromosome 13, but no rings or 12q13-15 changes, and 14 had various other aberrations. Ring chromosomes were found in all cytogenetically abnormal lipomas histologically classified as atypical and in nine tumors classified as typical lipoma or spindle cell lipoma. Recombinations between 12q13-15 and a few other bands or segments were seen more than once: 3q27-28 (15 tumors), 2p22-24 and 2q35 (four tumors), 1p32-34 and 13q12-14 (three tumors), and 5q33 (two tumors). Recombinations of 12q13-15 with 2q35 and 13q12-14 have not been described before. Of eight tumors with chromosome 13 aberrations, five had loss of 13q material. Aberrations of 12q13-15, 6p, and/or chromosome 13 were found simultaneously in nine tumors. Two to four samples from the same tumor were investigated in 29 tumors with clonal aberrations. Thirteen of these tumors displayed clonal evolution, also noted in another 17 tumors in which only one sample had been investigated. Thus clonal evolution occurred in 30% of the tumors and was particularly frequent in atypical lipomas.

Adolescent↗

PubMed2001

Genetic evolution in the metastatic progression of human pancreatic cancer studied by CGH.

Metastases are thought to be derived from emerging clones within primary tumors. Although the concept of the clonal evolution of cancer is well defined, the genetic grounds and significance of this process in human cancer progression are still poorly understood. To gain insight into the genetic basis and clonal evolution underlying the metastatic progression of human pancreatic cancer in vivo, we analyzed by comparative genomic hybridization (CGH) chromosomal imbalances in seven metastases originated in nude mice and their three corresponding orthotopically xenografted human pancreatic tumors. All metastases were found to be closely related to the corresponding orthotopic implant, adding many additional changes to the already altered copy number profile of the pancreatic tumors. Recurrent metastasis-specific alterations included gains at 16cen-q22 and 17q21-qter. CGH results from paired specimens strongly suggest that the majority of additional genetic alterations present in metastases are likely to be present in subclones in the primary tumor.

Animals↗