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ABSTRACT: We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1-PLAG1 gene fusions in which the 5'-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis.
Oncogene 06/2008; 27(21):3072-80. · 6.37 Impact Factor
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ABSTRACT: Extraskeletal myxoid chondrosarcomas (EMCs) are characterized by recurrent t(9;22) or t(9;17) translocations resulting in fusions of the NH2-terminal transactivation domains of EWS or TAF2N to the entire TEC protein. We report here an EMC with a novel translocation t(9; 15)(q22;q21) and a third type of TEC-containing fusion gene. The chimeric transcript encodes a protein in which the first 108 amino acids of the NH2-terminus of the basic helix-loop-helix (bHLH) protein TCF12 is linked to the entire TEC protein. The translocation separates the NH2-terminal domain of TCF12 from the bHLH domain as well as from a potential leucine zipper domain located immediately downstream of the breakpoint. These results demonstrate that the NH2-terminal transactivation domains of EWS or TAF2N are not unique in their ability to convert the TEC protein into an oncogenically active fusion protein, and that they may be replaced by a domain from a bHLH protein that presumably endows the fusion protein with similar functions.
Cancer Research 01/2001; 60(24):6832-5. · 7.86 Impact Factor
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ABSTRACT: We have previously shown (K. Kas et al, Nat. Genet., 15: 170-174, 1997) that the developmentally regulated zinc finger gene pleomorphic adenoma gene 1 (PLAG1) is the target gene in 8q12 in pleomorphic adenomas of the salivary glands with t(3;8)(p21;q12) translocations. The t(3;8) results in promoter swapping between PLAG1 and the constitutively expressed gene for beta-catenin (CTNNB1), leading to activation of PLAG1 expression and reduced expression of CTNNB1. Here we have studied the expression of PLAG1 by Northern blot analysis in 47 primary benign and malignant human tumors with or without cytogenetic abnormalities of 8q12. Overexpression of PLAG1 was found in 23 tumors (49%). Thirteen of 17 pleomorphic adenomas with a normal karyotype and 5 of 10 with 12q13-15 abnormalities overexpressed PLAG1, which demonstrates that PLAG1 activation is a frequent event in adenomas irrespective of karyotype. In contrast, PLAG1 was overexpressed in only 2 of 11 malignant salivary gland tumors analyzed, which suggests that, at least in salivary gland tumors, PLAG1 activation preferentially occurs in benign tumors. PLAG1 over-expression was also found in three of nine mesenchymal tumors, i.e., in two uterine leiomyomas and one leiomyosarcoma. RNase protection, rapid amplification of 5'-cDNA ends (5'-RACE), and reverse transcription-PCR analyses of five adenomas with a normal karyotype revealed fusion transcripts in three tumors. Nucleotide sequence analysis of these showed that they contained fusions between PLAG1 and CTNNB1 (one case) or PLAG1 and a novel fusion partner gene, i.e., the gene encoding the transcription elongation factor SII (two cases). The fusions occurred in the 5' noncoding region of PLAG1, leading to exchange of regulatory control elements and, as a consequence, activation of PLAG1 gene expression. Because all of the cases had grossly normal karyotypes, the rearrangements must result from cryptic rearrangements. The results suggest that in addition to chromosomal translocations and cryptic rearrangements, PLAG1 may also be activated by mutations or indirect mechanisms. Our findings establish a conserved mechanism of PLAG1 activation in salivary gland tumors with and without 8q12 aberrations, which indicates that such activation is a frequent event in these tumors.
Cancer Research 03/1999; 59(4):918-23. · 7.86 Impact Factor
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ABSTRACT: The cytogenetic observations in 97 new cases of pleomorphic adenomas are reported. They were all studied by in vitro technique using enzymatic pretreatment of the explanted material. The results, together with 26 previously reported cases studied by the same method (series II), were compared with a group of 130 adenomas (series I) investigated in cultures of only mechanically dispersed material. The results showed that in series II there was a substantial reduction of normal stemlines, an increase of cases with t(3;8)(p21;q12) and, in particular, of those with other 8q12 involvement. There was a similar frequency of cases with 12q13-15 aberrations in both series whereas, in series II, there was a moderate increase of the cases with "unique" abnormal stemlines. In comparison the German material, comprising 220 cases also studied by the enzymatic method, revealed a much higher frequency of cases with a normal stemline and a much lower frequency of adenomas with 8q12-involvement and of cases with unique stemlines. The results emphasize the need and importance of a meticulous documentation of all details of the in vitro technique used, for instance: explantation methods, composition of media, growth periods in vitro, and methods of harvest.
Cancer Genetics and Cytogenetics 06/1997; 95(1):9-15. · 1.39 Impact Factor
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ABSTRACT: The cytogenetical observations in a cultured parotid pleomorphic adenoma are presented. The patient had received treatment with X-rays for an infectious disorder in the same region about 50 years earlier. A polyclonal chromosomal pattern was disclosed with predominance of unique structural deviations. We have observed a similar chromosomal picture in a previously reported adenoma. This patient had also been treated with X-rays about 50 years earlier. The findings in these two cases suggest that many, perhaps all, pleomorphic adenomas are either congenital or arise very early in life. Their clinical manifestation at strongly varying time points in adulthood would then depend on accumulated mutational effects of unknown oncogenic agents.
Oncology Reports 11/1996; 3(6):1075-7. · 1.84 Impact Factor
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Hereditas 02/1996; 125(2-3):297-8. · 0.79 Impact Factor
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Cancer Genetics and Cytogenetics 03/1995; 79(2):188. · 1.39 Impact Factor
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ABSTRACT: 122 human uterine leiomyomas, representing the main chromosomal aberrations seen in these tumours, were analyzed by Southern blotting. Probes for the four oncogenes, gli, fos, jun, and met, all localized in or close to the chromosomal breakpoints in leiomyomas, were used. In only one single leiomyoma, with a 7p+q- marker, was there evidence of rearrangement of one of the oncogenes, namely met.
International Journal of Oncology 11/1994; 5(5):1093-7. · 2.40 Impact Factor
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ABSTRACT: Chromosomal studies of a cultured parotid sebaceous lymphadenoma showed two abnormal cell groups, one with trisomy 9 (15% of the metaphases) and one with inconsistent structural deviations (10%). FISH analysis showed that the trisomic clone was actually larger (36%) than that revealed by chromosomal studies. The sebaceous lymphadenoma represents the fourth type of benign salivary gland tumor to show clonal chromosomal deviations.
Oncology Reports 05/1994; 1(3):561-2. · 1.84 Impact Factor
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ABSTRACT: The chromosomes of a human benign chondroblastoma of the jaw were studied by in vitro technique. Approximately one-third of the analyzed cells had a normal karyotype. The remaining two-thirds constituted an abnormal monoclonal population with a complex and balanced translocation. The observations are different from those in previously studied benign primary bone tumors. The breakpoint in 22q, however, is similar or very close to that observed in two extraskeletal myxoid chondrosarcomas earlier reported.
Cancer Genetics and Cytogenetics 02/1992; 58(1):14-7. · 1.39 Impact Factor
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ABSTRACT: The chromosomes of a polymorphous low-grade adenocarcinoma originating from a pleomorphic adenoma of the parotid gland were studied. Three successful preparations were performed. A minor fraction of cells showed normal karyotypes and some cells only inconsistent, usually numerical, deviations. The remaining cells constituted an abnormal monoclonal population with an unusual and very extensive karyotypic variability. The origin of most marker chromosomes could be wholly or partly clarified. Five different subclones could be distinguished on basis of different specific marker chromosomes. The characteristics of the marker sets suggested a closely interrelated derivation of the subclones. The results also provide insight as to the influence of random factors and/or differential growth rate on the chromosomal picture observed in in vitro systems. The present chromosomal observations showed no similarities either to the cytogenetical findings in the five previously reported salivary gland adenocarcinomas or to the deviations seen in the single studied case of carcinoma ex-pleomorphic adenoma.
Cancer Genetics and Cytogenetics 09/1991; 55(1):19-29. · 1.39 Impact Factor
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ABSTRACT: Chromosomal observations by banding technique in 18 short-term cultured human uterine leiomyomas are reported. Half of the tumors had a primary or secondary abnormal stemline. They were usually characterized only by structural changes, in particular reciprocal translocations or insertions. Reviewing already published cases together with the new material confirmed that the aberrations in abnormal stemlines predominantly affected chromosomes 1, 2, 6, 7, 12, 14, and X. In these chromosomes the regions 1p36, 2p24, 6p12-21, 7q21-31, 12q13-15, 14q22-24, and the short arm of the X chromosome were preferentially affected. As in two other thoroughly studied human benign tumors, the pleomorphic adenoma and the meningioma, the very specific but sometimes complex chromosomal aberrations in leiomyomas could well be events of primary evolutionary importance. Likewise, in cases with a normal stemline, it is possible that comparable changes in the corresponding specific chromosomal regions have occurred at a submicroscopic level. Ascertaining this possibility, as well as the role of the aberrations with regard to the benign nature of the tumors, must be the focus of future analysis using molecular techniques.
Cancer Genetics and Cytogenetics 02/1990; 44(1):1-13. · 1.39 Impact Factor
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ABSTRACT: Cytogenetic studies in thyroid neoplasia were performed by G-banding of chromosome preparations obtained from the in vitro cultures of nine adenomas, one follicular carcinoma, five papillary carcinomas, and two medullary carcinomas. Complex structural chromosome aberrations were found in one adenoma. Two more adenomas, both composed of Hürthle cells, showed multiple numerical chromosome deviations with trisomy 4 and tetrasomy 7 in common. Six metastasizing carcinomas were characterized by normal stemlines, which indicates that malignancy in thyroid neoplasia cannot be excluded by cytogenetic techniques used currently. Comparisons between cytogenetic findings and cytophotometric DNA measurements in the material studied illustrate that euploid tumors represent a heterogenous group including cases with various gross structural chromosome aberrations of yet unknown clinical significance. Further studies of additional material with long-term follow-up are called for by our findings of structural and numerical chromosome aberrations in follicular neoplasms that are benign according to histologic criteria.
Cancer 09/1989; 64(3):680-5. · 4.77 Impact Factor
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ABSTRACT: The chromosomes from three uterine tumours found in the same patient, two benign leiomyomas (L22 and L23) and a low-grade stroma cell sarcoma with leiomyomatous differentiation (L24), were studied by banding technique. L23 had an abnormal stemline distinguished by triosomy 12. The sarcoma showed a stemline with the same 7q-marker as L23 plus a marker del (12)(q13-24). A comparison with cytogenetically studied myomas collected from the literature showed (1) that there are at least three different recurrent, primary, gross chromosomal changes, viz. t(12;14)(q14-15;q23-24), t(1;2)(p36;p24) and del(7)(q22-31) and that there exist at least five further types of primary chromosomal deviations. The sarcoma showed aberrations identical or closely related to the recurrent structural deviations in myomas. These observations indicate a similar evolutionary pattern in benign and malignant leiomyomatous tumours.
Apmis 03/1989; 97(2):143-6. · 1.99 Impact Factor
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ABSTRACT: The chromosomes of a human gastric leiomyosarcoma were studied in preparations from short-term cultures. The tumor had a triploid-near-triploid modal population characterized by extensive numerical and structural changes. Of these deviations, del(1)(p12-13), monosomy 14, and underrepresentation of chromosomes 18 and 22 were abnormalities in common with two of the three previously studied leiomyosarcomas of the small bowel.
Cancer Genetics and Cytogenetics 03/1989; 37(2):215-20. · 1.39 Impact Factor
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ABSTRACT: The chromosomes from two human uterine lipoleiomyomas, L25 and L26, from the same patient, were studied by a banding technique applied to preparations from short-term cultures. Both tumors displayed the same pseudodiploid stemline characterized by the reciprocal translocation t (5; 12) (q12; q24). These observations coincide with the previous finding that the largest subgroup of typical leiomyomas with an abnormal stemline are characterized by a long-arm change of one chromosome No. 12. The combined results support the previously advanced hypothesis that different histologic subtypes of uterine leiomyomas are derived from a common totipotential stem cell. This interpretation also fits with a proposed theory about the derivation of malignant leiomyomatous uterine neoplasms.
Virchows Archiv B Cell Pathology 02/1989; 57(1):77-9.
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ABSTRACT: Chromosomes were studied in cultured material from two different areas of a human mucoepidermoid carcinoma. The detailed banding analyses showed no less than 41 different karyotypes. Comparisons between these revealed (1) that the tumour probably had originated with a normal, diploid stemline; (2) that the progression had mainly proceeded by steps in a hyperdiploid direction, by, as a rule, sequential numerical deviations; and (3) that there existed at least eight further, different, evolutionary products from the original stemline. The complex progressional pattern disclosed in the present case contrasts with cytogenetical data documented for most human benign as well as malignant tumour types.
Hereditas 02/1989; 110(1):75-8. · 0.79 Impact Factor
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ABSTRACT: Cytogenetic observations by banding methods in 56 new cases of human benign pleomorphic adenomas are reported. Thirty of the cases (series I) were studied in preparations from primary cultures established from cells growing out from mechanically dispersed tumor pieces. The remaining 26 cases (series II) were analyzed in preparations from primary cultures established from enzymatically pretreated material. The use of the latter method resulted in a decrease in the frequency of cases with a normal stemline from about 53% to about 19%. However, the general characteristics of the aberrations observed in abnormal stemlines in both series agreed well. The minor differences observed consisted of a higher frequency of recurrent t(3;8)(p21;q12) in series II and, in the same series, fewer cases showing an involvement of 8q or 12q. The present results emphasize the importance of molecular studies of, in particular, the regions 8q12, 12q13-15, and 3p21.
Cancer Genetics and Cytogenetics 08/1988; 33(2):229-44. · 1.39 Impact Factor
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ABSTRACT: The cytogenetical findings from a parametrial leiomyoma are presented. The results, together with those of five previously presented cases, show obvious differences when compared to the chromosomal findings in uterine myomas. Ontogenic factors are proposed to be causative for the cytogenetical differences.
Anticancer research 17(3C):2121-2. · 1.73 Impact Factor
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ABSTRACT: Detailed observations by banding technique in 21 cultured human benign uterine leiomyomas are reported. More than half of the tumors (51%) had a primary or secondary abnormal stemline. The abnormal stemlines were usually characterized only by structural changes, in particular reciprocal translocations. These translocations, as well as instances of inversions, predominantly affected the chromosome types Nos. 1,2 and 12 and preferentially the regions 1p36, 2p24 and 12q14-15. Available data concerning cytogenetical deviations in benign human tumor types indicate that, in contrast to most malignant neoplasms, they are characterized by comparatively few and simple, either numerical or, more frequently, structural changes. The biological implications of these deviations are rapidly emerging as one of the most urgent areas for future studies with molecular techniques.
Anticancer research 8(4):621-6. · 1.73 Impact Factor
