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| 3. |
- Bartuma, Hammurabi, et al.
(författare)
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Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype
- 2007
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:6, s. 594-606
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Tidskriftsartikel (refereegranskat)abstract
- Conventional lipomas harbor karyotypic changes that could be subdivided into four, usually mutually exclusive, categories: rearrangement, in particular through translocations, of chromosome bands 12q13-15, resulting in deregulation of the HMGA2 gene, loss of material from or rearrangement of chromosome 13, supernumerary ring or giant marker chromosomes, and aberrations of chromosome band 6p21. In the present study, 272 conventional lipomas, two-thirds of them deep-seated, with acquired clonal chromosome changes were assessed with regard to karyotypic and clinical features. A nonrandom distribution of breakpoints and imbalances could be confirmed, with 83% of the cases harboring one or more of the previously known cytogenetic hallmarks. Correlation with clinical features revealed that lipomas with rings/giant markers were larger, occurred in older patients, were more often deep-seated, and seemed to have an increased tendency to recur locally, compared with tumors with other chromosome aberrations. The possible involvement of the HMGA2 gene in cases that did not show any of the characteristic cytogenetic changes was further evaluated by locus-specific metaphase fluorescence in situ hybridization (FISH) and RT-PCR, revealing infrequent cryptic disruption of the gene but abundant expression of full length or truncated transcripts. By FISH, we could also show that breakpoints in bands 10q22-23 do not affect the MYST4 gene, whereas breakpoints in 6p21 or 8q11-12 occasionally target the HMGA1 or PLAG1 genes, respectively, also in conventional lipomas.
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| 4. |
- Bartuma, Hammurabi, et al.
(författare)
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Expression levels of HMGA2 in adipocytic tumors correlate with morphologic and cytogenetic subgroups.
- 2009
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Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 8:Jun 9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The HMGA2 gene encodes a protein that alters chromatin structure. Deregulation, typically through chromosomal rearrangements, of HMGA2 has an important role in the development of several mesenchymal neoplasms. These rearrangements result in the expression of a truncated protein lacking the acidic C-terminus, a fusion protein consisting of the AT-hook domains encoded by exons 1-3 and parts from another gene, or a full-length protein; loss of binding sites for regulatory microRNA molecules from the 3' untranslated region (UTR) of HMGA2 has been suggested to be a common denominator. METHODS: Seventy adipocytic tumors, representing different morphologic and cytogenetic subgroups, were analyzed by qRT-PCR to study the expression status of HMGA2; 18 of these tumors were further examined by PCR to search for mutations or deletions in the 3'UTR. RESULTS: Type (full-length or truncated) and level of expression varied with morphology and karyotype, with the highest levels in atypical lipomatous tumors and lipomas with rearrangements of 12q13-15 and the lowest in lipomas with 6p- or 13q-rearrangements, hibernomas, spindle cell lipomas and myxoid liposarcomas. All 18 examined tumors showed reduced or absent expression of the entire, or parts of, the 3'UTR, which was not due to mutations at the DNA level. CONCLUSION: In adipocytic tumors with deregulated HMGA2 expression, the 3'UTR is consistently lost, either due to physical disruption of HMGA2 or a shift to production of shorter 3'UTR.
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- Beverloo, H. Berna, et al.
(författare)
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Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13)
- 2001
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Ingår i: Cancer Research. - 1538-7445. ; 61:14, s. 5374-5377
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we and others reported a recurrent t(7;12)(q36;p13) found in myeloid malignancies in children < or =18 months of age and associated with a poor prognosis. Fluorescence in situ hybridization studies mapped the 12p13 breakpoint to the first intron of ETV6 and narrowed down the region of 7q36 involved. By using the sequences made public recently by the Human Genome Project, two candidate genes in 7q36 were identified: the homeobox gene HLXB9 and c7orf3, a gene with unknown function. Reverse transcription-PCR of two cases with t(7;12), using primers for c7orf3 and ETV6, was negative. However, reverse transcription-PCR for HLXB9-ETV6 demonstrated alternative splicing; the two major bands corresponded to fusion of exon 1 of HLXB9 to exons 2 and 3, respectively, of ETV6. The reciprocal ETV6-HLXB9 transcript was not detected. It remains to be elucidated if the leukemic phenotype is attributable to the formation of the HLXB9-ETV6 fusion protein, which includes the helix-loop-helix and E26 transformation-specific DNA binding domains of ETV6 or to the disruption of the normal ETV6 protein.
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- Brandal, Petter, et al.
(författare)
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Detection of a t(1;22)(q23;q 12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepithelioma
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47:7, s. 558-564
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1-8 of the 5'-end of EWSR1 and exons 5-9 of the 3-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1.
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- Brandal, Petter, et al.
(författare)
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t(19;22)(q13;q12) Translocation Leading to the Novel Fusion Gene EWSRI-ZNF444 in Soft Tissue Myoepithelial Carcinoma
- 2009
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 48:12, s. 1051-1056
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Tidskriftsartikel (refereegranskat)abstract
- Myoepithelial neoplasms of soft tissue have only recently been acknowledged as a separate diagnostic entity. To know based on histological appearance whether these tumors are benign or malignant is often difficult, and their tumorigenic mechanisms remain poorly understood. We report a myoepithelial carcinoma with an aberrant near-diploid karyotype, 43 similar to 47,XX,add(1)(p34)x2,add(3)(q27)x2,del(12)(q22),+add(18)(p11)x2,del(22)(q 11),+r, found in cells cultured from a lung metastasis. The deletion in 22q led us to search by molecular cytogenetic means for possible EWSRI rearrangements, and eventually a novel chimeric gene consisting of the 5'-end of EWSRI (22q12) and the 3'-end of ZNF444 (19q13) was found. How the new fusion gene contributes to tumorigenesis is unknown, but the finding of an EWSRI rearrangement suggests that this, possibly even the EWSRI-ZNF444, is a defining pathogenetic feature of at least a subset of these tumors. (C) 2009 Wiley-Liss, Inc.
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- Broberg Palmgren, Karin, et al.
(författare)
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Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15.
- 2002
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Ingår i: International Journal of Oncology. - 1019-6439. ; 21:2, s. 321-326
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Tidskriftsartikel (refereegranskat)abstract
- Rearrangements of chromosome bands 12q13-15 are frequent in various benign mesenchymal and epithelial tumors, and the gene HMGA2 seems to be the most common target within this chromosome region. In the majority of cases, the rearrangements result in a fusion of the first three exons of HMGA2 with different translocation partners. Despite the large number of HMGA2 mutations that have been reported, very little is known about the fusion partners. In this study, we have characterized a recurrent fusion of the first three exons of HMGA2 5' to the G protein-coupled receptor gene (RDC1) in lipomas with rearrangements involving chromosome bands 2q35-37 and 12q13-15, one of several recurrent chromosomal rearrangements in lipomas. The functional impact of the fusion is truncation of HMGA2, because the RDC1 part contributes with a stop codon one amino acid downstream of the breakpoint. The breakpoint within RDC1 was localized in a previously uncharacterized exon of the gene, and our data suggest that RDC1 is subject to alternative splicing.
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| 9. |
- Dahlén, Anna, et al.
(författare)
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Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas
- 2003
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Ingår i: Modern Pathology. - 1530-0285. ; 16:11, s. 1132-1140
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue and skeletal chondromas are rare entities, and only 21 cases with abnormal karyotypes have been reported. A survey of these, and 10 new cases reported herein, showed that the 12q13-15 segment is nonrandomly involved in structural rearrangements in chondromas. The HMGA2 (HMGI-C) locus in 12q15 is frequently rearranged in other benign mesenchymal tumors, and this study aimed at characterizing the expression of HMGA2 in chondromatous tumors. The material consisted of 8 soft tissue and 6 skeletal chondromas, as well as of 14 skeletal chondrosarcomas. All cases had been cytogenetically analyzed. Expression of HMGA2 could be assessed by RT-PCR in 8 chondromas and 13 chondrosarcomas. HMGA2 was expressed in 4 of six soft tissue chondromas, all displaying 12q-rearrangements at cytogenetic analysis. A truncated transcript (exons 1-3), but not a full-length (exons 1-5) transcript, was detected in three of them, suggesting activation through an intragenic rearrangement. One soft tissue chondroma had a t(3;12)(q27;q15), and the RT-PCR analysis revealed an HMGA2-LPP fusion transcript, composed of HMGA2 exons 1-3 and LPP exons 9-11. An identical fusion transcript previously has been identified in lipoma and pulmonary chondroid hamartoma. In the fourth soft tissue chondroma, a full-length transcript was detected, indicating expression of at least one intact allele. Both skeletal chondromas expressed HMGA2. In one of them, a full-length transcript was detected, even though 12q was cytogenetically unaffected. A truncated or full-length transcript was found in 8 of 13 chondrosarcomas, 4 of which displayed 12q rearrangements. Possibly, cryptic rearrangements were present among the many complex marker chromosomes in the remaining 4 cases.
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