1.
Broberg Palmgren, Karin, et al.
(författare)
Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15.
2002
Ingår i: International Journal of Oncology. - 1019-6439. ; 21:2, s. 321-326
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.
2.
Panagopoulos, Ioannis, et al.
(författare)
Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses.
2002
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 99:4, s. 560-567
Tidskriftsartikel (refereegranskat) abstract
Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13;q12) resulting in a chimeric EWS/ATF1 gene in which the 3'-terminal part of EWS at 22q is replaced by the 3'-terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level. In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT-PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1-4, were identified. The most frequent chimeric transcript (type 1) was an in-frame fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in-frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in-frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out-of-frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out-of-frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out-of-frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1. While a simple end-to-end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion.
3.
Panagopoulos, Ioannis, et al.
(författare)
Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma.
2002
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 35:4, s. 340-352
Tidskriftsartikel (refereegranskat) abstract
Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences. Copyright 2002 Wiley-Liss, Inc.
