| 1. |
- Storlazzi, CT, et al.
(author)
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A novel chromosomal translocation t(3;7)(q26;q21) in myeloid leukemia resulting in overexpression of EVI1
- 2004
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In: Annals of Hematology. - : Springer Science and Business Media LLC. - 1432-0584 .- 0939-5555. ; 83:2, s. 78-83
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Journal article (peer-reviewed)abstract
- The EVI1 proto-oncogene encodes a nuclear zinc finger protein that acts as a transcription repressor factor. In myeloid leukemia it is often activated by chromosomal rearrangements involving band 3q26, where the gene has been mapped. Here we report two leukemia cases [a chronic myeloid leukemia blast crisis (CML-BC) and an acute myeloid leukemia (AML) M4] showing a t(3;7)(q26;q21) translocation in a balanced and unbalanced form, respectively. Fluorescent in situ hybridization (FISH) analysis revealed that both patients showed a breakpoint on chromosome 3 inside the clone RP11-33A1 containing the EVI1 oncogene and, on chromosome 7, inside the clone RP11-322M5, partially containing the CDK6 oncogene which is a D cyclin-dependent kinase gene, observed to be overexpressed and disrupted in many hematological malignancies. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed overexpression of EVI1 in both cases, but excluded the presence of any CDK6/EVI1 fusion transcript. CDK6 expression was also detected. Together, these data indicate that EVI1 activation is likely due not to the generation of a novel fusion gene with CDK6 but to a position effect dysregulating its transcriptional pattern.
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| 2. |
- Storlazzi, CT, et al.
(author)
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Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma
- 2005
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 117:6, s. 1055-1057
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Journal article (peer-reviewed)abstract
- Neurofibroma is a benign tumor originating from Schwann cells in peripheral nerve sheaths and may occur as a sporadic tumor or as part of the dominantly inherited tumor syndrome NF1. NF1 is caused by constitutional mutations in the NF1 gene, located in chromosome band 17q11 Whereas the involvement of the NF1 gene in neurofibroma development in NF1 patients has been fairly well characterized, the significance of inactivation of this gene in sporadic neurofibromas remains less well investigated. Inactivation of both copies of NF1 has been described in a few neurofibromas from NF1 patients, and LOH at the same locus has been reported in additional cases. In the present study, we report the cytogenetic and molecular cytogenetic findings in a sporadic neurofibroma that at G-banding analysis showed a translocation between one chromosome 2 and the long arms of both copies of chromosome 17. FISH analysis using a set of 3 BAC clones covering the entire coding region of NF1 revealed the complete loss of one allele and the deletion of the 5' portion of the second allele as a result of 2 translocation events. To the best of our knowledge, this represents the first demonstration of a somatic biallelic inactivation of the NF1 gene in neurofibroma, providing further evidence for the importance of NF1 inactivation also in sporadic neurofibromas.
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| 3. |
- Storlazzi, CT, et al.
(author)
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MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene
- 2006
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:6, s. 933-942
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Journal article (peer-reviewed)abstract
- Double minutes (dmin)-circular, extra-chromosomal amplifications of specific acentric DNA fragments-are relatively frequent in malignant disorders, particularly in solid tumors. In acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), dmin are observed in similar to 1% of the cases. Most of them consist of an amplified segment from chromosome band 8q24, always including the MYC gene. Besides this information, little is known about their internal structure. We have characterized in detail the genomic organization of 32 AML and two MDS cases with MYC-containing dmin. The minimally amplified region was shown to be 4.26 Mb in size, harboring five known genes, with the proximal and the distal amplicon breakpoints clustering in two regions of similar to 500 and 600 kb, respectively. Interestingly, in 23 (68%) of the studied cases, the amplified region was deleted in one of the chromosome 8 homologs at 8q24, suggesting excision of a DNA segment from the original chromosomal location according to the 'episome model'. In one case, sequencing of both the dmin and del(8q) junctions was achieved and provided definitive evidence in favor of the episome model for the formation of dmin. Expression status of the TRIB1 and MYC genes, encompassed by the minimally amplified region, was assessed by northern blot analysis. The TRIB1 gene was found over-expressed in only a subset of the AML/MDS cases, whereas MYC, contrary to expectations, was always silent. The present study, therefore, strongly suggests that MYC is not the target gene of the 8q24 amplifications.
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| 4. |
- Storlazzi, CT, et al.
(author)
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Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic delineation of the tumor-specific translocation t(X;6)(q13-14;q22)
- 2006
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 118:8, s. 1972-1976
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Journal article (peer-reviewed)abstract
- Subungual exostosis is a benign bone- and cartilage-producing tumor occurring in the hands and feet of children and young adults. The recent identification of a recurrent chromosomal translocation t(X;6)(q24-q26;q15-21) in short-term-cultured tumor cells strongly suggests that subungual exostosis is a neoplastic lesion caused by rearrangement of genes in the two breakpoints. To identify the genes that are critical for neoplastic transformation, we have studied five subungual exostoses by interphase or metaphase FISH. The results of these analyses demonstrated a clustering of the breakpoints to the regions harboring the collagen genes COL12A1 and COL4A5 in chromosome bands 6q13-14 and Xq22, respectively. Furthermore, in all but one case, these two genes were shown to colocalize on the derivative chromosomes X and 6, strongly suggesting that at least one of them is consistently involved in the formation of a chimeric fusion gene or in the exchange of regulatory sequences. Because collagen molecules are important for tissue remodeling during physiologic growth and differentiation, both COL12A1 and COL4A5 constitute good candidate target genes in the pathogenesis of subungual exostosis. Further investigations on the transcript level are required to elucidate the functional outcome of the t(X;6) translocation in subungual exostoses. (c) 2005 Wiley-Liss, Inc.
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