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F Mitelman

Publications and source records attributed to F Mitelman.

At least 55 records · Page 3Linked to original sources
PubMed1999

The structure and dynamics of ring chromosomes in human neoplastic and non-neoplastic cells.

Acquired ring chromosomes have been found in most types of human neoplasia, with a frequency approaching 10% in malignant mesenchymal tumours. In this study, the composition and dynamics of ring chromosomes were analysed in eight cases of acute myelogenous leukaemia, 17 solid tumours, and five cases with constitutional rings. Chromosomal banding and fluorescence in situ hybridisation were performed to determine the content and the structural heterogeneity of the rings. Telomeric repeats were detected using peptide nucleic acid probes or primed in situ labelling, whereas centromeric activity was evaluated by detection of kinetochore proteins. Mitotic instability was assessed by the frequency of anaphase bridges. The results suggest that human ring chromosomes can be structurally and functionally divided into two categories. In the first of these, size variation is minimal and rearrangement at cell division is uncommon. The majority of such rings contain subtelomeric sequences. Constitutional ring chromosomes and most rings in leukaemias belong to this group, whereas only a few mesenchymal tumours exhibit rings of this type. The second category consists of rings with amplified sequences, primarily from chromosome 12, characteristically occurring in atypical lipomatous tumours and other subtypes of low or borderline malignant mesenchymal neoplasms. Variation in size and number is extensive, and breakage-fusion-bridge events occur at a high frequency. Abnormalities in pericentromeric sequences are common and, in some cases, kinetochores assemble in the absence of alphoid DNA. We conclude that it is not only the ring structure per se or the neoplastic nature of the host cell that determines ring instability, but probably also the functional role of the genes carried in the ring.

Abnormalities, Multiple↗
PubMed1999

Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group.

Soft-tissue tumors have proved to be a fruitful area for the identification of reproducible cytogenetic aberrations, especially among pediatric round-cell sarcomas and lipomatous tumors. Thus far, however, data regarding sarcomas of monomorphic spindle cell type have been limited and somewhat disappointing, with the notable exception of synovial sarcoma. As part of an ongoing international collaborative study, 130 karyotyped spindle-cell sarcomas were reviewed and classified histologically, without knowledge of the clinical and karyotypic data, with the aim of identifying objective correlations between morphology, karyotype, and clinical parameters. Clonal chromosomal abnormalities were identified in 82 cases studied (63%), but only in the group of synovial sarcomas was there clear correlation between the cytogenetic findings, in the form of a consistent t(X;18)(p11;q11), and morphology. Among leiomyosarcomas (41 cases) and malignant peripheral nerve sheath tumors (MPNSTs; 27 cases) as well as in individual examples of rarer entities, there was a general tendency for karyotypic complexity associated with frequent loss or rearrangement of chromosome arms 1p, 10p, 11q, 12q, 17p, and 22q. Rearrangements of 17q (the region of the NF1 gene) were seen in 9/27 (33%) of MPNSTs. Among nine cases of solitary fibrous tumor (in which previous cytogenetic data are very limited) no consistent aberrations were identified. We conclude that, with the exception of synovial sarcoma, most spindle-cell sarcomas share with pleomorphic sarcomas the tendency for karyotypic complexity. There was no indication (in most of these lesions) that detectable cytogenetic aberrations could either facilitate their diagnosis or help to determine prognosis. There is a clear need to further study and understand the significance of multiple chromosomal abnormalities in this group of mesenchymal neoplasms with the particular goal of determining their role in the process of tumor development.

Adolescent↗
PubMed1999

Cytogenetic monoclonality in multifocal uroepithelial carcinomas: evidence of intraluminal tumour seeding.

Twenty-one multifocal urinary tract transitional cell carcinomas, mostly bladder tumours, from a total of six patients were processed for cytogenetic analysis after short-term culturing of the tumour cells. Karyotypically related, often identical, cytogenetically complex clones were found in all informative tumours from each case, including the recurrent tumours. Rearrangement of chromosome 9, leading to loss of material from the short and/or the long arm, was seen in all cases, indicating that this is an early, pathogenetically important event in transitional cell carcinogenesis. The presence of related clones with great karyotypic similarity in anatomically distinct tumours from the same bladder indicates that multifocal uroepithelial tumours have a monoclonal origin and arise via intraluminal seeding of viable cancer cells shed from the original tumour. Later lesions may develop also from cells shed from the so called second primary tumours. The relatively complex karyotypes seen in all lesions from most cases argue that the seeding of tumour cells is a late event that succeeds the acquisition by them of multiple secondary genetic abnormalities.

Aged↗
PubMed1999

A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender.

During the 18-yr period 1976-93, a population-based series of 1586 adults with suspected or confirmed hematological malignancies were successfully cytogenetically investigated at a single center. Eighty-six cases were excluded due to unretrievable medical records or if analyzed only in remission or at relapse. The remaining 1500 medical records were reviewed regarding morphology and clinical parameters in order to investigate possible associations between karyotypic pattern (normal, 1, 2 or complex anomalies; specific abnormalities) and gender, age and morphological subgroups. The impact of time-period, i.e. 1976-87 vs. 1988-93, and referring center on cytogenetic findings was also studied. A total of 372 acute myeloid leukemias (AML), 389 myelodysplastic syndromes (MDS), 64 acute lymphoblastic leukemias (ALL) and 262 chronic myeloid leukemias (CML) were identified, altogether 1087 cases. Patients with other (n=261) or no hematological malignancies (n = 152) were excluded from the present analysis. Cytogenetic abnormalities were detected in 52% AML, 51 % MDS, 68% ALL and 97% CML, frequencies that did not differ significantly between the 2 time periods or referring centers. No significant age- or gender-related differences in karyotypic patterns were discerned in AML, MDS, ALL or CML, whereas the karyotypic patterns varied among the FAB groups in both AML (p= 0.001) and MDS (p < 0.001). The specific abnormalities t(8;21), t(15;17) and inv(16) were more common (p < 0.001) in younger AML patients and 5q- was more frequent in females with MDS (p<0.001). These findings indicate, in contrast to previous series, that neoplasia-associated karyotypic aberrations are not more common among older patients or in males.

Adult↗
PubMed1999

Prognostic implications of cytogenetic aberrations in diffuse large B-cell lymphomas.

A single institution series of 81 consecutive, cytogenetically analyzed, diffuse large B-cell lymphomas (DLBL), the majority of which treated with anthracycline-containing combination chemotherapy, were reviewed retrospectively to investigate whether the karyotypic pattern or certain abnormalities correlate with survival. Clonal chromosome changes were found in 79 of the 81 cases. The prognostic impact of the following aberrations, all suggested in previous studies to be associated with either shorter or longer survival, were tested: 1q21-23 breakpoints, +2/dup(2p), +3/dup(3p), +5, +6, 6q21-25 breakpoints, monosomy 7/der(7p)/i(7q), trisomy 7, 14q11-12 breakpoints, monosomy 17/der(17p)/i(17q), trisomy 18, > 4 marker chromosomes, > 4 breakpoints, and > or = 10 abnormalities. Univariate analysis showed that a breakpoint at 1q21-23 or trisomy 6 was associated with a shorter survival. However, when adjusted for age, stage, performance status and lactate dehydrogenase level, none of the cytogenetic aberrations had an independent prognostic value. Thus, the present investigation provides no support for any of the above-mentioned abnormalities being of prognostic importance in DLBL.

Adult↗
PubMed1999

Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas.

Cytogenetic analysis was performed on 363 biopsy specimens with histologically confirmed diffuse large B-cell lymphoma (DLBCL), consecutively ascertained at the Memorial Sloan-Kettering Cancer Center, New York, between 1984 and 1994. Among 248 samples successfully karyotyped, clonal chromosomal abnormalities were noted in 215 (87%). The salient cytogenetic features of DLBCL from this analysis comprised the following. Breakpoints clustered, in decreasing frequency, at 10 recurring sites: 14q32, 18q21, 1q21, 3q27, 1p36, 8q24, 3p21, 6q21, 1p22, and 22q11. Of these, deletion breaks affecting bands 3p2 and 1p22 and translocation breaks affecting bands 14q32, 3q27, and 1q2 were frequent and distinctive for this subset of lymphomas. Translocations affecting band 14q32 were noted in 110 cases (51%) of which 42 (20%) had t(14;18)(q32;q21), 21 (10%) had t(8;14)(q24;q32) or t(8;22)(q24;q11), 14 (6.5%) had t(3;14)(q27;q32) or t(3;22)(q27;q11), and 33 (15%) had other rearrangements of 14q32. Among 144 new translocations detected in the entire group, the breakpoints in 19 were recurrent and clustered at three sites: 1q21, 3q27, and 14q32. Regions of common cytogenetic deletions were identified at 11 sites, 1p36, 1p33-34, 1p31, 1q32, 3p25-26, 3p21, 3q21, 6q15, 6q21, 6q23-24, and 7q32, suggesting possible loss of candidate tumor suppressor genes associated with DLBCL development. Of these, only those at 6q21, 6q23, and 7q32 have previously been described in lymphoid neoplasms. The group of DLBCL with translocations affecting band 14q32 showed a significantly different pattern of additional cytogenetic changes compared to the group lacking such translocation. This new comprehensive cytogenetic characterization provides the basis for investigations aimed at identifying molecular mechanisms as well as the clinical impact of cytogenetic changes in DLBCL.

Chromosome Aberrations↗
PubMed1999

Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group.

The karyotypes of 44 specimens from 35 patients with localized (n = 19) or diffuse (n = 16) tenosynovial giant cell tumors were studied. The majority of cases in both categories (11 of 19 localized; 12 of 16 diffuse) displayed clonal chromosomal aberrations, with a complex karyotype in three cases and a simple chromosomal aberration in the others. No difference in the distribution of karyotypic abnormalities was found between the localized and diffuse form except for trisomies (usually of chromosomes 5 and/or 7), which were more frequent in the diffuse type. The short arm of chromosome 1 (1p11-13) was most frequently rearranged, with 7 of 11 localized and 7 of 12 diffuse lesions affected. These findings indicate that the localized and diffuse forms of tenosynovial giant cell tumor might represent two morphologic manifestations of the same entity. The high frequency of clonal chromosomal abnormalities, with a clustering of structural rearrangements to 1p11-13, suggests that this disease is most likely neoplastic in nature and paves the way to search for gene(s) that might be involved in its development.

Adolescent↗
PubMed1999

Cytogenetic polyclonality in hematologic malignancies.

The present study was undertaken to ascertain the frequency of cytogenetic polyclonality in various hematologic malignancies and to investigate whether morphologic subgroup, age, gender, or previous genotoxic exposure influences the incidence. Among 2,243 cytogenetically investigated hematologic malignancies, 10 acute myeloid leukemias (AML), 5 myelodysplastic syndromes (MDS), 2 acute lymphoblastic leukemias (ALL), 1 acute undifferentiated leukemia (AUL), 1 atypical Philadelphia chromosome-negative (Ph-) chronic myeloid leukemia (CML), 1 chronic myeloproliferative disorder (CMD), and 1 chronic lymphoproliferative disorder (CLD) with karyotypically unrelated clones were identified, constituting 2.6% of AML, 1.6% of MDS, 0.8% of ALL, 13% of AUL, 9.1% of Ph- CML, 1.5% of CMD, and 2.8% of CLD with chromosomal abnormalities. In contrast to the cytogenetic features, the X-inactivation pattern was monoclonal in the two informative female patients that could be investigated. Among 17,733 karyotypically aberrant published cases surveyed, significant frequency differences (P < 0.001) were discerned: 1.7% of 6,526 AML, 3.4% of 2,391 MDS, 0.4% of 1,920 Ph+ CML, 2.9% of 856 CMD, 0.9% of 4,226 ALL, and 5.8% of 1,814 CLD displayed unrelated clones. The incidence of cytogenetic polyclonality did not differ significantly among the MDS, CMD, or ALL subgroups, between males and females, between children (< 16 years) and adults, or between B- and T-cell ALL, whereas the frequencies varied among the AML FAB types (P < 0.05), among the different CLD entities (P < 0.001), and between B- and T-cell CLD (P < 0.001). Furthermore, the incidence was higher in therapy-related AML and MDS than in de novo AML and MDS (P < 0.001 and P < 0.01, respectively).

Adolescent↗
PubMed1998

Cancer predictive value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health.

The cytogenetic endpoints in peripheral blood lymphocytes: chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronuclei (MN) are established biomarkers of exposure for mutagens or carcinogens in the work environment. However, it is not clear whether these biomarkers also may serve as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed for SCE or MN. A collaborative study between the Nordic and Italian research groups, will enable a more thorough evaluation of the cancer predictivity of the cytogenetic endpoints. We here report on the establishment of a joint data base comprising 5271 subjects, examined 1965-1988 for at least one cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers, occupational exposures and smoking, will be assessed in a case-referent study within the study base.

Biomarkers, Tumor↗
PubMed1998

Cytogenetic findings in invasive breast carcinomas with prognostically favourable histology: a less complex karyotypic pattern?

Seventeen invasive primary breast carcinomas of histological types usually considered to be prognostically favourable (2 medullary, 3 papillary, 3 tubular, and 9 mucinous carcinomas) were analysed as part of an ongoing study of the cytogenetics of breast cancer. Thirteen of the tumours (7 mucinous, 2 medullary, 2 papillary, and 2 tubular carcinomas) showed clonal chromosome aberrations. Trisomy 7 and i(1q) were present as sole and recurrent aberrations in the mucinous tumours. The 2 tubular carcinomas and I papillary carcinoma had simple numerical changes only, whereas the second papillary tumour had a balanced translocation as the sole anomaly. Both medullary carcinomas had chromosome numbers in the triploid range, with clones displaying structural and numerical changes. Our data, especially when collated with information on previously published cases of mucinous, papillary, tubular, and medullary breast carcinomas, show that the former 3 histological types, in keeping with their recognised prognostic advantage, appear to exhibit relatively simple karyotypic changes, i.e., numerical aberrations, balanced translocations, and near-diploid chromosome numbers. Medullary carcinomas on the other hand, appear to have more complex karyotypes, similar to those described for the more common ductal and lobular subtypes of breast carcinoma.

Adenocarcinoma, Mucinous↗
PubMed1998

Chromosomal abnormalities in two bladder carcinomas with secondary squamous cell differentiation.

Two secondary squamous cell carcinomas of the bladder (i.e., tumors that originated from primary transitional cell carcinomas) were examined cytogenetically. Both tumors showed complex karyotypes with many of the same aberrations that have formerly been described in transitional cell carcinomas. Monosomy 9, trisomy 7, and rearrangements of chromosomes 3, 8, 10, 13, and 17 were common to both tumors. Among other changes that have been implicated in bladder carcinogenesis, an isochromosome for 5p was seen in one tumor and loss of 11p material in the other. Our findings indicate that secondary squamous cell carcinomas of the bladder are karyotypically indistinguishable from advanced transitional cell carcinomas of the same organ. The putative genetic changes that steer the differentiation of the neoplastic epithelium in the direction of squamous cells thus remain unknown.

Aged↗
PubMed1998

Genomic amplification of CCND2 is rare in non-Hodgkin lymphomas.

Cyclin D2, encoded by CCND2 at 12p13, takes part in the regulation of the cell cycle and has been suggested as a candidate for gene amplification in lymphoid malignancies. CCND2 is often overexpressed in chronic B-cell disorders, and we recently detected genomic amplification of the chromosomal region containing CCND2 in two of three investigated non-Hodgkin lymphomas (NHLs) with cytogenetic abnormalities involving 12p. In the present study, 58 NHLs without karyotypic evidence of 12p aberrations were analyzed by fluorescence in situ hybridization with probes for CCND2. No genomic amplification was found, strongly suggesting that this abnormality is rare in such NHLs.

Chromosome Aberrations↗
PubMed1998

Comparison of chromosomal patterns with clinical features in 165 lipomas: a report of the CHAMP study group.

Soft tissue lipomatous tumors are morphologically heterogeneous. Various morphologic features are associated with specific chromosomal patterns and clinical features such as age, sex, and tumor site, location, and size. Simple lipomas are known to be karyotypically heterogeneous, but this has not been correlated with clinicopathological features. In 165 cases of solitary soft tissue lipoma, short-term cultures were analyzed cytogenetically. The karyotypes were divided into the following groups: normal karyotype; 12q13-15 aberrations; 6p rearrangements; 13q rearrangements, 8q11-13 aberrations; ring or giant marker chromosomes or both; other aberrations. The tumors were reexamined morphologically without knowledge of the karyotypic or clinical data. An abnormal chromosomal pattern was observed in 129 of 165 cases (78%): in 75 of 90 (83%) lipomas in the extremities and in 43 of 63 (68%) trunk wall lipomas. Chromosomal aberrations were present in 69 of 90 (77%) subcutaneous tumors and in 59 of 64 (80%) deep tumors. A normal karyotype was twice as frequent in tumors in patients under 30 years of age than in those from older individuals (6 of 16 vs. 30 of 149, 40% resp. 20%). Apart from the finding that normal karyotypes were more common in patients younger than 30 years, there was no significant association between cytogenetic pattern and patient sex or age or tumor localization, size, or depth. The pathogenetic basis and clinicopathologic relevance (if any) of the cytogenetic subtypes among benign lipomas remain unexplained.

Adolescent↗
PubMed1998

Expression analysis and chromosomal mapping of a novel human gene, APRIL, encoding an acidic protein rich in leucines.

Clone 120041 was selected from the EST database for sequence similarity to DEK and SET proteins rearranged in leukemias. The ends of the cDNA were isolated by RACE technique. The assembled cDNA encodes an LRR-containing protein of 251 amino acids designated APRIL (acidic protein rich in leucines). APRIL has high similarity to human pp32, also named PHAPI (bovine I[PP2A]1), and to rat LANP, respectively. APRIL shows tissue-specific expression as shown by Northern blot analysis. It was localized to 15q25 by FISH.

Amino Acid Sequence↗
PubMed1998

Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue.

Angiosarcomas are rare malignant vascular tumors, most commonly found in the skin or superficial soft tissue. We found clonal chromosome aberrations in four short-term cultured angiosarcomas. Two cases were diagnosed as epithelioid angiosarcomas, and one as postmastectomy angiosarcoma. Two of the tumors were deep-seated and two were superficial. Angiosarcomas from deep, soft tissue are extremely rare and have never been cytogenetically investigated before. The chromosome number ranged from hypodiploid to hypertriploid. When the results from the present study were combined with data on the four previously reported cytogenetically aberrant angiosarcomas, the most frequently rearranged chromosomes were 5, 7, 8, 13, 15, 20, 22, and the Y chromosome. Recurrent changes, each found in three of these eight angiosarcomas, were gains of 5pter-p11, 8p12-qter, and 20pter-q12, losses of 7pter-p15 and 22q13-qter, and -Y in two of three men.

Adult↗
PubMed1998

Cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features: a report of the CHAMP Study Group. Chromosomes and MorPhology.

With the aim of identifying objective cytogenetic-morphologic correlations, we evaluated 46 pleomorphic soft tissue sarcomas (mainly diagnosed originally as malignant fibrous histiocytomas) with clonal chromosome aberrations both cytogenetically and morphologically as part of an international collaborative study. By detailed histopathologic examination, most cases could be categorized into specific tumor types. Eight sarcomas were diagnosed as lipogenic (4 pleomorphic, 1 combined pleomorphic and myxoid/round cell, and 3 dedifferentiated liposarcomas), 19 as myogenic [11 leiomyosarcomas, 1 rhabdomyosarcoma, 4 myosarcomas not otherwise specified (NOS), and 3 probable myosarcomas NOS], 8 as myxofibrosarcomas, 1 as a malignant peripheral nerve sheath tumor, 1 as malignant mesenchymoma, 1 as extraskeletal osteosarcoma, I as sarcoma resembling proliferative fasciitis, and 7 as pleomorphic sarcomas NOS. In a three-grade system, 10 tumors were grade 2 and 36 were grade 3. The majority had highly complex karyotypes. A total of 24 recurrent abnormalities (defined by their presence in at least five cases) were detected: ring chromosomes, homogeneously staining regions (hsr) and/or double minute chromosomes (dmin), and structural rearrangement of 22 different chromosome bands or regions. The frequency and distribution of the recurrent karyotypic features were uneven. Grade 3 tumors displayed, on average, more aberrations per case than did grade 2 tumors. Nine of the selected abnormalities, including hsr/dmin and rearrangements of 19p13 and 19q13, were found only among the high-grade tumors. When the tumors were subdivided according to lineage of differentiation, the highest frequency of aberrations was seen in pleomorphic sarcomas NOS, followed by myxofibrosarcomas, myogenic sarcomas, and lipogenic sarcomas. None of the selected rearrangements was, however, specific for any of these subgroups. The sole consistent cytogenetic-morphologic association was that all three dedifferentiated liposarcomas had multiple abnormal clones, at least one of which contained supernumerary ring chromosomes. Due mainly to karyotype complexity, it therefore seems unlikely that cytogenetic analysis can assist in the differential diagnostic subclassification of pleomorphic sarcomas, nor was there any clear-cut indication that the karyotypic picture could be used to predict clinical outcome. Although the mean number of recurrent chromosome aberrations was almost twice as high in sarcomas that gave rise to metastases as among those that did not, no particular aberration was restricted to either of the two subgroups.

Adult↗
PubMed1998

Frequent rearrangements of chromosomes 1, 7, and 8 in primary liver cancer.

Fifteen primary liver carcinomas (PLCs), including 12 hepatocellular carcinomas and three cholangiocellular carcinomas, were investigated cytogenetically after short-term culture. Ten tumors displayed clonal chromosomal abnormalities, whereas only normal karyotypes were detected in four cases, and one sample failed to grow in vitro. Structural rearrangements most often involved chromosomes 1, 7, and 8 and chromosome bands 1p36, 1q25, 3q10, 5q13, 6p10, 7p15, 7q22, 7q32, 8q10, 8q13, 14q10, and 17p11. Frequent genomic imbalances included gains of 1q, 3q, 6p, 7p, and 8q and losses of 1p, 8p, 10q, 14p, 17p, and 19p. A compilation of findings for all 19 cytogenetically abnormal PLCs reported to date, including the present cases, reveals that structural aberrations particularly affect 1p11, 1p22, 1p32, 1p34, 1p36, 1q25, 7p15, 7q22, 8q10, 8q13, 14q10, 16q24, and 17p11, and that the abnormalities frequently result in overrepresentation of 1q, 3q, 6p, 7p10-14, 8q, and 17q and underrepresentation of 1p34-36, 6q27, 7q32-qter, 8p, 13p, 14p, 16q24, and 17p. These genomic regions are likely to harbor genes of importance in hepatocarcinogenesis, and the present cytogenetic mapping may hence be of value for further molecular genetic investigations of PLC.

Adolescent↗