| 1. |
- 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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| 2. |
- Bartuma, Hammurabi, et al.
(författare)
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Cytogenetic and molecular cytogenetic findings in lipoblastoma.
- 2008
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 183:1, s. 60-63
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Tidskriftsartikel (refereegranskat)abstract
- Lipoblastoma is a rare benign tumor that arises from embryonic adipose tissue and usually occurs in young children. Here, we present a review of available cytogenetic data and the karyotypes of 10 new cases of lipoblastoma, of which 7 could be studied further by fluorescence in situ hybridization (FISH) with regard to the involvement of the PLAG1 gene. All seven tumors with clonal aberrations harbored breakpoints in 8q11 approximately q13, in agreement with literature data. Including previously published cases, 33/40 (82%) lipoblastomas had rearrangement of the 8q11 approximately q13 region. These rearrangements target the PLAG1 gene, which becomes upregulated through promoter swapping. FISH revealed that five of seven cases in our series had a rearrangement of the PLAG1 gene. Occasionally, there can be difficulties in distinguishing a lipoblastoma from a conventional lipoma or a myxoid liposarcoma. As 8q11 approximately q13 rearrangements have been reported in only 3% of conventional lipomas and never in myxoid liposarcoma, cytogenetic analysis or FISH for the PLAG1 gene can provide useful differential diagnostic information.
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| 3. |
- Bartuma, Hammurabi
(författare)
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CYTOGENETIC AND MOLECULAR GENETIC CHARACTERIZATION OF LIPOMAS
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The focus of this thesis was to study cytogenetic and molecular genetic aberrations in lipomas. For this purpose, chromosome banding analysis, fluorescence in situ hybridization (FISH), as well as high resolution single nucleotide polymorphism (SNP)–arrays were used to identify recurrent chromosomal aberrations in lipomas. The possible molecular targets for these aberrations were further studied through conventional and quantitative polymerase chain reaction (PCR and qRT-PCR) analyses and global gene expression profiling. Lipomas were found to be characterized by recurrent chromosome aberrations, frequently involving the HMGA2 gene. Furthermore, HMGA2 was found to be differentially expressed in different cytogenetic and morphologic subgroups of adipocytic tumors, with the highest expression levels occurring in atypical lipomatous tumor / well differentiated liposarcoma; these tumors usually have amplification, in the form of supernumerary ring chromosomes, of the chromosomal region where the HMGA2 gene is located. The second highest expression levels of HMGA2 were seen in conventional lipomas with structural rearrangements of chromosome region 12q13-15. Tumors expressing the full-length gene did not express the 3’ untranslated region (3’UTR), suggesting that the aberrant HMGA2 expression of the full-length gene was due to loss of regulatory sequences in the 3’UTR. Another frequent cytogenetic aberration in conventional lipomas was deletion of the long arm of chromosome 13. Using SNP-arrays, this deletion could be further delineated. Two minimal deleted regions (MDR) in chromosome band 13q14 were found in spindle cell lipomas (SCLs) and one in conventional lipomas; the latter MDR overlapped with one of those in SCLs. By global gene expression analysis and qRT-PCR one gene, C13orf1, was found to be expressed at significantly lower levels in conventional lipomas, and one microRNA (miR-16-1) turned out to be a potential target in SCLs. Further studies are needed to validate if the functional outcome of the 13q-deletions is loss of one or both of these genes.
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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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| 5. |
- Bartuma, Hammurabi, et al.
(författare)
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Fusion of the FUS and CREB3L2 genes in a supernumerary ring chromosome in low-grade fibromyxoid sarcoma.
- 2010
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 199:2, s. 143-146
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Tidskriftsartikel (refereegranskat)abstract
- Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recurrences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary ring chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such ring chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the ring contained material from chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with ring chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that ring formation in LGFMS is correlated with tumor progression.
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| 6. |
- Bartuma, Hammurabi, et al.
(författare)
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Gene expression and single nucleotide polymorphism array analyses of spindle cell lipomas and conventional lipomas with 13q14 deletion.
- 2011
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 50, s. 619-632
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Tidskriftsartikel (refereegranskat)abstract
- Spindle cell lipomas (SCL) are circumscribed, usually s.c. tumors that typically occur on the posterior neck, shoulder, and back of middle aged men. Cytogenetically, almost all SCL are characterized by deletions of chromosome arm 13q, often in combination with loss of 16q. Deletions of 13q are seen also in approximately 15% of conventional lipomas. Through single nucleotide polymorphism (SNP) array analyses, we identified two minimal deleted regions (MDR) in 13q14 in SCL. In MDR1, four genes were located, including the tumor suppressor gene RB1. MDR1 in SCL overlapped with the MDR detected in conventional lipomas with 13q14 deletion. In MDR2 in SCL there were 34 genes and the two microRNA (miRNA) genes miR-15a and miR-16-1. Global gene expression analysis was used to study the impact of the deletions on genes mapping to the two SCL-associated MDR. Five genes (C13orf1, DHRS12, ATP7B, ALG11, and VPS36) in SCL and one gene (C13orf1) in conventional lipomas with 13q-deletions were found to be significantly underexpressed compared with control tissues. Quantitative real-time PCR showed that miR-16-1 was expressed at lower levels in SCL than in the control samples. No mutations were found at sequencing of RB1, miR-15a, and miR-16-1. Our findings further delineate the target region for the 13q deletion in SCL and conventional lipomas and show that the deletions are associated with down-regulated expression of several genes, notably C13orf1, which was the only gene to be significantly down-regulated in both tumor types. © 2011 Wiley-Liss, Inc.
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| 7. |
- Mandahl, Nils, et al.
(författare)
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HMGA2 and MDM2 expression in lipomatous tumors with partial, low-level amplification of sequences from the long arm of chromosome 12.
- 2011
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Ingår i: Cancer Genetics. - : Elsevier BV. - 2210-7762. ; 204:10, s. 550-556
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Tidskriftsartikel (refereegranskat)abstract
- Ordinary lipomas are cytogenetically characterized primarily by simple balanced chromosome aberrations with stable morphologies, most of which affect chromosome segment, 12q13-15, where the HMGA2 gene plays a key pathogenetic role. Atypical lipomatous tumors (ALTs) display supernumerary ring or giant marker chromosomes with amplification of several genes including HMGA2 and MDM2. A study of HMGA2 expression in a variety of adipocytic tumors showed aberrant expression in lipomas with 12q13-15 aberrations and ring chromosomes as well as in ALTs and well-differentiated liposarcomas (WDLSs), and frequent differential expression of HMGA2 exons 1-2 versus that of exons 4-5. A minor subset of adipocytic tumors harbors unbalanced karyotypes with extra copies of 12q sequences in structures that are not giant marker or ring chromosomes. Out of a series of ten such tumors, three lipomas and four ALTs with more than two copies of 12q13-15 and breakpoints in 12q13-15 could be analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) to find out whether HMGA2 and MDM2 expression was more similar to the levels seen in lipomas with cytogenetically balanced aberrations of 12q13-15, or to ALTs with giant ring or marker chromosomes. One of two ALTs with more complex, hyperdiploid karyotypes had expression levels closer to those seen in ALT, whereas the remaining six cases were similar to lipomas with 12q13-15 changes and ring chromosomes. Differential expression was seen in two ALTs and all three lipomas. Two cases showed MDM2 expression levels similar to those found among WDLSs, two cases showed levels similar to those found among lipomas, whereas the remaining three cases displayed intermediate expression levels. The studied cases represent intermediates between lipoma and ALT, insofar as they shared 12q13-15 rearrangements and karyotypic stability with lipomas and gain of 12q sequences with ALTs. Neither of these characteristics can be used to discriminate between lipoma and ALT.
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