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PubMed1996

Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation.

In chronic lymphocytic leukemia (CLL), clonal rearrangement of the immunoglobulin heavy chain locus (IgH) provides a useful marker for the detection of minimal residual disease (MRD) after treatment. At the time of initial presentation, DNA from patients with CLL was polymerase chain reaction (PCR)-amplified using consensus Variable (VH) and Joining (JH) region primers using complementarity determining region III consensus region primers or a panel of VH family-specific framework region 1 (FR1) primers. The clonal product was directly sequenced and patient-specific probes constructed using N region nucleotide sequences. We amplified and sequenced the CDRIII region and designed patient specific oligonucleotide probes for the detection of MRD in 55 of 66 patients (84%, 90% Confidence Intervals (CI): 74% to 90%) with poor prognosis CLL referred for autologous and allogeneic bone marrow transplantation (BMT). To determine the clinical utility of this technique, PCR amplification was performed on patient samples at the time of and following autologous (21 patients) and allogeneic (10 patients) BMT in whom serial bone marrow samples obtained after BMT were available for analysis. We show that the persistence of MRD after BMT is associated with increased probability of relapse. In all cases that have relapsed to date, the IgH CDRII region was identical at the time of initial presentation and at relapse suggesting that clonal evolution of the IgH locus is unusual in this disease. The finding that a significant number of patients remain disease free and with no evidence of PCR-detectable MRD after BMT suggests that high-dose therapy may contribute to improved outcome in selected patients with CLL.

Base Sequence↗
PubMed1996

Analysis of the complementary determining region III of the immunoglobulin heavy chain locus in acute lymphoblastic leukemia in Chilean children.

We have analyzed the sequence of 40 VDJ rearrangements of the immunoglobulin heavy chain gene locus on 32 unselected children from Chile with precursor B cell ALL at diagnosis. Rearrangements were derived by PCR with VH gene family-specific primers and sequenced directly. The number of VDJ rearrangements, and the pattern of VH, DH and JH gene usage was identical to the one reported by groups from developed countries. CDR3 regions represented an unbiased repertoire; VH to JH joinings were in frame in 36% of cases. Absent N nucleotides in the DJ border, suggestive of fetal origin of ALL, were seen in 9/40 rearrangements but they did not correlate with younger age. More than one rearrangement was sequenced in six patients, representing independent events with no signs of clonal evolution. One patient was analyzed at first bone marrow relapse showing persistence of one rearrangement and evolution of a second one which conserved the DJ border. The subset of B cell precursors which suffer malignant transformation to ALL appear to be common in different parts of the world.

Adolescent↗
PubMed1996

A novel quantitative 'stretch PCR assay', that detects a dramatic increase in telomerase activity during the progression of myeloid leukemias.

Telomerase activation is important for carcinogenesis. However, the timing and magnitude of the activation during cancer development are unknown. In this study, a new PCR-based method for measuring telomerase activity was developed and shown to be very useful for quantitative analysis of human telomerase. Using this assay, blood or bone marrow cells from healthy donors, and patients with chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) were examined as to their relative activity. Telomerase activity present in normal peripheral blood cells was generally very low. However, significant activity was detected occasionally in samples derived from younger healthy donors. Striking telomerase activation was observed at the time of the blastic crisis in CML: no samples from chronic phase cases showed significant activity, while all cases with a well established crisis showed strong activity. Most AML cases were telomerase-positive. Quantitative analyses revealed that the relative titer varied among the AML patients, from as low as found in normal cells to as high as found in cell lines. However, a tendency that the activity was higher in relapsed cases than in fresh ones was suggested. In summary, telomerase was activated during the progression of the clinical stages in leukemias. This observation suggests that shortened telomeres and increased telomerase activity might be necessary for cancer cells to undergo clonal evolution towards more malignant phenotypes in advanced stages.

Adult↗
PubMed1996

Activation of quiescent ABL-transduced hemopoietic stem cells.

Chronic myelogenous leukemia (CML) is a hemopoietic stem cell disorder in which an activated ABL oncogene is expressed and has been shown to play an important role in disease pathogenesis. A mouse model has been established in which hemopoietic stem cells (HSCs) transduced with a retrovirus vector carrying an activated ABL oncogene can be analysed. Using this model, we now report that abl-transduced HSCs can be quiescent without causing a disease for an extended period of time. Recipient mice were able to survive more than one treatment of 5-fluorouracil (5-FU) at a dose that normally eliminates cycling hemopoietic progenitor cells; subsequently, transduced HSCs could become activated and undergo clonal expansion, resulting in abl-induced leukemic development. The disease developed in these mice was transplantable. Upon engraftment into secondary mice, previously unidentified abl-transduced HSC clones appeared. These data suggest the presence of an abl-suppressive mechanism in HSCs and have important implications to the pathogenesis of stem cell diseases and leukemic clonal evolution.

Animals↗
PubMed1997

Evidence of clonal divergence in colorectal carcinoma.

BACKGROUND: The aim of this study was to investigate the generation of DNA ploidy diversity in different stages of colorectal carcinoma development. METHODS: DNA flow cytometry was performed on tissue samples from 20 colorectal adenomas, 38 colorectal carcinomas, 30 lymph node metastases, and 70 hematogenous metastases. RESULTS: DNA aneuploidy was detected in 30% of the adenomas, 82% of the primary colorectal tumors, 57% of the lymph node metastases, 92% of the liver metastases, and 100% of the other distant hematogenous metastases. Multiple DNA tumor stemlines were found in 10%, 39%, 29%, 24%, and 40%, respectively. Sixty-two percent of the DNA tumor stemlines detected in the lymph node or liver metastases were also present in the primary tumors. In primary carcinomas and lymph node metastases, the DNA index distribution had a bimodal shape with a minimum at the 1.2-1.4 region. In the hematogenous metastases, a higher percentage of hypertetraploid stemlines was found. CONCLUSIONS: The emergence of DNA aneuploidy as well as clonal divergence seems to take place during the transition from adenoma to carcinoma. The DNA aneuploid stemlines formed during this phase remain relatively stable over time, although ongoing clonal evolution at distant metastatic tumor sites cannot be completely ruled out.

Adenoma↗
PubMedDate not supplied

Peripheral blood picture in primary hypocellular refractory anemia and idiopathic acquired aplastic anemia: an additional tool for differential diagnosis.

BACKGROUND AND OBJECTIVE: Hypoplastic myelodysplastic syndromes (MDS) are being reported with increasing frequency. Aplastic anemia (AA) needs to be differentiated from hypoplastic MDS particularly primary hypoplastic refractory anemia (PHRA) because of the impact on management and prognosis. This distinction may be morphologically difficult even with careful marrow examination which may provide insufficient material due to extreme hypocellularity. The value of peripheral blood (PB) parameters in making the distinction between AA and PHRA is not well studied. In this work, we attempt to examine peripheral blood findings as an additional tool for differentiating PHRA from acquired idiopathic AA. METHODS: PB findings in ten cases of PHRA, which are selected based on the following: less than 30% cellularity, multilineage dysplasia and/or clonal cytogenetic abnormality, are compared to ten cases of classic AA. The PB is examined for automated parameters, differential white cell count, morphologic changes in red cells, white cells, platelets, and the presence of circulating blasts, megakaryocytic fragments and micromegakaryocytes. RESULTS: AA patients tend to have lower platelet and monocytic counts and higher lymphocytic percentages. The following morphologic findings are seen only in PHRA but not in AA: hypochromic red cells, left shift, circulating blasts, hypersegmentation with long filaments, hypogranular, ring, and pelgeroid neutrophils, Dohle bodies, circulating micromegakaryocytes and megakaryocytic fragments. INTERPRETATION AND CONCLUSIONS: We conclude that careful examination of peripheral blood may provide sufficient information to allow for the distinction between PHRA and AA early in the course of the disease. Similarly, patients with classic AA who subsequently develop unusual blood findings during routine follow up should be suspected of having a clonal evolution which needs to be confirmed by marrow examination and cytogenetic analysis.

Adult↗
PubMed1997

p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is thought to arise from a noninvasive neoplastic precursor, the pancreatic intraductal lesion (PIL). Mutations of the K-ras gene are known to occur in PILs, but their high prevalence among PILs within the general population probably limit the use of K-ras as a marker of eventual clinical risk. In search of genetic constellations that might indicate the progression of some PILs toward an invasive phenotype, mutations at both the K-ras and p16 genes were sought within PILs of 10 pancreata resected for adenocarcinoma. K-ras mutations were present in most PILs and in nearly all PILs having nuclear atypia. In half of the patients, two or more unique K-ras mutations were identified among distinct PILs, which is evidence for the separate clonal evolution of multiple pancreatic neoplasms within individual patients. p16 alterations (one homozygous deletion and three point mutations) were found in 4 of the 10 carcinomas; these four pancreata harbored p16 alterations in three of nine PILs, of which one was a "histologically early" lesion. Two patients had p16 alterations in PILs matching those of the associated carcinomas. p16 mutations were not found in PILs of pancreata having wild-type p16 in the carcinoma, nor were they found in ducts having normal histology. It is suggested that alterations of the p16 gene affect a subset of PILs that contain mutations of the K-ras gene and that these mutations might identify high-risk precursors of the invasive malignancy.

Adenocarcinoma↗
PubMed1997

NPM/ALK fusion mRNA expression in Hodgkin and Reed-Sternberg cells is rare but does occur: results from single-cell cDNA analysis.

BACKGROUND: The translocation t(2;5)(p23;q35) leads to the fusion of the nucleophosmin gene (NPM) on chromosome 5q35 to the recently described receptor kinase ALK on 2p23. It is characteristic of a subgroup of CD30+ large-cell anaplastic non-Hodgkin's lymphoma (ALCL). Since some cases of Hodgkin's disease (HD) and ALCL share common features, a common pathogenesis has been proposed in a report of the expression of NPM/ALK fusion mRNA in 11/13 Hodgkin's lymphomas. PATIENTS AND METHODS: We approached this question by micro-manipulatory isolation of single Hodgkin and Reed-Sternberg (H-RS) cells and subsequent RT-PCR amplification of NPM/ALK fusion cDNA from these single cells. RESULTS: Specificity of cell selection was shown by the HD-specific pattern of EBV-gene expression in single H-RS cells. In 4 out of 7 cases, NPM/ALK fusion cDNA was detected in the RNA from whole lymph node tissue. In 2 out of 9 cases, NPM/ALK fusion sequences were amplified from single H-RS cells, albeit in a very low frequency (< 5%). CONCLUSIONS: These data indicate that NPM/ALK fusion transcripts do not play an early role in the pathogenesis of HD. Whether the rare expression of NPM/ALK is the result of clonal heterogeneity or an indication for clonal evolution and progression toward ALCL can only be answered by the repeated analysis of indicator cases during the course of the disease.

Adolescent↗
PubMed1997

Chromosome abnormality in solid and cystic tumor of the pancreas.

We report a case of a solid and cystic tumor of the pancreas with chromosomal abnormalities. The patient, a 13-yr-old girl, successfully underwent surgical excision and has been asymptomatic for more than 10 months. The tumor had two parameters suggesting malignant potential; a local invasion into a bile duct, and high mitotic activity. Chromosomal analysis showed two complex abnormalities, of which double loss of X chromosomes and trisomy for chromosome 3 were common. The complexity and polyclonality may stem from a clonal evolution. The observed abnormalities may provide a crucial clue to the understanding of the developmental process of this neoplasm.

Adolescent↗
PubMed1995

Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation.

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.

Acute Disease↗
PubMed1997

Specific histologic and cytogenetic evidence for in vivo malignant transformation of murine host cells by three human prostate cancer cell lines.

The chromosomal constitutions of three murine cell lines that developed in vitro from tumors that grew in nude mice after orthotopic and ectopic injections of three human prostate tumor cell lines were examined by histopathology, conventional G-banding, and with fluorescence in situ hybridization techniques. All three murine cell lines showed unique marker chromosomes involving mouse chromosome 12, with a common break point. Histopathologic evidence from a murine prostate gland into which SP 3031 cells had been injected indicated dysplastic glandular epithelium and carcinomatous areas. These observations further indicate that: (a) human prostate tumors are capable of transforming host organ cells, (b) host cells have specific chromosomal alterations that may be associated with transformation, and (c) the process of host cell transformation can be demonstrated in histological sections. Although cancer cell heterogeneity and drug-resistant phenotypes are caused by additional genetic alterations and clonal evolution of the original tumor, transformation of the host's distant organ cells may also contribute because most therapies are directed only to the original cancer cells.

Animals↗
PubMed1998

Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors.

BACKGROUND: The finding of a cytogenetic-pathologic correlation between complex karyotypes and high grade cartilaginous tumors has been reported. However, few cytogenetic reports exist regarding benign or low grade lesions. A subset of low grade malignant cartilaginous tumors is characterized by locally aggressive behavior but no metastatic potential. Because the histopathologic distinction between benign, borderline, or low grade malignant cartilaginous lesions can be difficult, the finding of additional tumor markers associated with the clinical behavior of borderline cartilaginous lesions could be clinically significant. METHODS: Four cartilaginous tumors, including an osteochondroma (OC), a chondromyxoid fibroma (CF), an enchondroma (EC), and a dedifferentiated chondrosarcoma (DCS), were cultured and harvested using short term, in situ culture techniques. Chromosome analysis was performed by conventional G-banding and fluorescence in situ hybridization was used to confirm G-banding. RESULTS: The stemlines of all four tumors showed multiple chromosome anomalies that included aberrations of 6q13-21. The OC showed a t(6;16)(q21;p13.3). The CF showed a complex rearrangement between the chromosome 6 homologues, resulting in an inv(6)(p25q23)t(6;6)(q23;q13). This tumor also showed the clonal evolution of telomeric associations resulting in duplications, deletions, and the formation of a ring 15. The EC showed a der(6)t(6;15)(q13;q11)t(15;22)(q22;q13) stemline and subclones with an unstable iso 17q that subsequently fused to both ends of chromosome 16. The DCS showed a del(6)(q13), r(9), +12 stemline. CONCLUSIONS: The cytogenetic findings of this study suggest the cytogenetic-pathologic correlation of complex karyotypes found in high grade cartilage tumors may extend to lower grade tumors with complex karyotypes. These findings further suggest that chromosome aberrations in the region of 6q13-21 may be associated with locally aggressive behavior in patients with cartilage tumors.

Adolescent↗
PubMed1998

Clonality of lymphomas at multiple sites in SJL mice.

SJL mice are an inbred strain of mice with a high incidence of spontaneous lymphomas of B-cell type often involving multiple abdominal organs, and are therefore a useful model for studying the clonal relationship among lymphomas at multiple sites. Thirteen SJL mice with well-developed tumors were killed at a median age of 56 weeks. Autopsy samples were taken from various enlarged lymphoid organs, and the histologic appearance of lymphomas was recorded. Using rearrangements of immunoglobulin genes (heavy and kappa-light chain genes) and integration patterns of murine leukemia virus as clonal markers, 7 of the 13 informative mice showed complete clonal identity among the different sites selected from each mouse; 5 of 13 mice demonstrated at least one shared clonal band with one or more markers being different among the different sites. The histologic appearance of the lymphomas from the various sites was found to be heterogeneous, even when there was clonal identity. These findings suggest that SJL lymphomas in multiple sites within one mouse are usually derived from a single clone but may show development of subclones within a major clonal population, thus supporting the notion that clonal evolution is a common event in the course of development of lymphoid neoplasia.

Animals↗
PubMed1998

Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas.

A high prevalence of chronic hepatitis C virus (HCV) infection has recently been shown in a subset of B-cell non-Hodgkin's lymphomas, most of which belong to the lymphoplasmacytoid lymphoma/immunocytoma subtype and are characterized by the production of a monoclonal IgM cryoglobulin with rheumatoid factor activity. To better define the stage of differentiation of the malignant B cell and to investigate the role of chronic antigen stimulation in the pathogenesis of the HCV-associated immunocytomas, we analyzed the variable (V) region gene repertoire in 16 cases with this type of tumor. The lymphoma-derived V gene sequences were successfully determined in 8 cases; 5 of them expressed the 51p1 VH gene in combination with the kv325 VL gene. Moreover, a monoclonal 51p1-expressing B-cell population was detected in 4 of the remaining immunocytomas by an allele-specific Ig gene fingerprinting assay, indicating that HCV-associated immunocytomas represent clonal proliferations of a highly selected B-cell population. Somatic mutations and intraclonal diversity were observed in all of the lymphoma V genes, and clonally related IgM and IgG VH transcripts indicative of isotype switching were present in one case. These findings are consistent with an antigen-driven process and support a role for chronic antigen stimulation in the growth and clonal evolution of HCV-associated immunocytomas.

Adult↗
PubMed1998

Cytogenetic comparison of primary tumors and lymph node metastases in breast cancer patients.

Chromosome banding analysis of primary tumors and axillary lymph node metastases from 10 breast cancer patients revealed abnormal karyotypes in all samples with cytogenetic similarities between the primary tumor and the metastasis in all informative pairs. Although karyotypically unrelated clones were also found in the lymph node samples, they were less numerous than in the primary tumors, indicating that there was more genetic heterogeneity among the neoplastic cells in the primary than in the secondary tumors. On the other hand, some of the clones had become more complex in the metastases as a result of clonal evolution, and by and large these metastatic breast cancer cases had more karyotypic anomalies than do unselected primary breast carcinomas. Among the aberrations occurring more frequently, and that consequently may predispose to disease spread, were losses of chromosomes 17 and 22 and homogeneously staining regions, a cytogenetic sign of gene amplification.

Adult↗
PubMed1998

Cytogenetic analysis shows that carcinosarcomas of the breast are of monoclonal origin.

Carcinosarcoma of the breast is a rare biphasic neoplasm composed of a carcinomatous component contiguous or admixed with a pleomorphic spindle cell component. The issues of the histogenesis and clonal composition of carcinosarcomas have long been debated. We present the first cytogenetic characterization of mammary carcinosarcomas by analysis of eight tumor samples from two patients with this disease. In the first case, the same karyotypically complex clone, as well as evidence of clonal evolution, was found in samples from three separate areas of the primary tumor. The analysis of one intramammary and one axillary lymph node metastasis from the same patient, both showing only the sarcomatous tumor component, also revealed the common complex stemline and one of the two sidelines found in the primary tumor. The carcinosarcoma of the second patient contained six complex but karyotypically related clones unevenly distributed among the three samples examined. From this case, cells belonging to the carcinomatous and sarcomatous tumor components were separated by differential sedimentation and culturing in specific growth media. Analysis of both fractions showed largely the same karyotype, although one of the subclones was restricted to the epithelial component. Our findings indicate that the epithelial and mesenchymal components of mammary carcinosarcomas are both part of the neoplastic parenchyma and that they have evolved from a single common stem cell, in agreement with the hypothesis that the tumors are of monoclonal origin.

Breast Neoplasms↗
PubMed1998

Genetic alterations in primary bladder cancers and their metastases.

Bladder cancer progression is thought to be associated with sequential genetic events. To search for the specific genetic changes associated with the metastatic process, comparative genomic hybridization was performed on 22 primary tumors and 24 metastases (10 distant and 14 nodal metastases) from 17 patients with stage pT2-4 bladder cancer. There was a striking similarity between the genetic alterations present in the primary and metastatic tumor samples from the same patient. The mean number of genetic changes/tumor was 12.2 for primary tumors and 11.7 for metastases. There was a strong concordance in the specific aberrations present in each patient's primary and metastatic lesions (mean, 75%). Concordance was also high among multiple sites from an individual primary tumor (mean, 96%) and multiple metastases from the same patient (mean, 75%). There were no specific genetic changes overrepresented in the metastases compared with their primary tumors. Genetic alterations present in more than 40% of tumors included gains on 6p, 8q, 10q, and 17q and losses involving 8p, 10q, and Y. Two regions of high-level amplification were common: (a) 10q22.1-q23.1 (32.6%); and (b) 17q11-21.3 (23.9%; the locus of erbB-2). A summary statistic was developed to quantitate the degree of clonal relationships between biopsies from the same patient. These data support a model in which minimal clonal evolution occurs in the metastatic tumor cell population after the metastatic event. When comparing primary cancers from patients with and without metastases, however, several unique genetic changes were identified in those cancers with metastases, suggesting that these loci may harbor genes important to the metastatic process.

Aged↗
PubMed1998

Clonal population structure of Colombian sylvatic Trypanosoma cruzi.

Isoenzyme variability and evidence of genetic exchange were evaluated in 75 wild stocks of Trypanosoma cruzi obtained from different hosts from 5 geographical regions within the endemic area in Colombia. Cluster analysis of genetic variability was attempted. Thirty-three multilocus enzyme genotypes (clonets) were identified from 75 stocks, 27 of which clustered with zymodeme Z1 and 6 with zymodeme Z3. Two stocks isolated from human infections showed the potential risk to rural communities in Colombia. The stocks exhibited departures from Hardy-Weinberg expectations, including both fixed heterozygote and fixed homozygote demes, where both segregation and recombination were absent. To inspect for population subdivision that might falsely imply clonality in these stocks, Wright's F statistics were calculated. Theta values (Fst) were significantly different from 0 when 33 clonets, 27 Z1-like clonets, and 5 geographical subpopulations were compared; thus, a significant amount of divergence has occurred between and within them. In addition, linkage disequilibrium was detected for most possible pairwise comparisons of loci. In conclusion, the above results all support a scenario of long-term clonal evolution in Colombian sylvatic T. cruzi populations.

Animals↗