| 1. |
- Gebre-Medhin, Samuel, et al.
(författare)
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Telomeric associations correlate with telomere length reduction and clonal chromosome aberrations in giant cell tumor of bone.
- 2009
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 124:2, s. 121-127
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Tidskriftsartikel (refereegranskat)abstract
- Giant cell tumor of bone (GCTB) is characterized cytogenetically by frequent telomeric associations (tas). To explore the mechanisms behind the formation of tas in GCTB and to investigate their karyotypic consequences, the frequencies of tas and clonal aberrations other than tas in 20 GCTBs were compared to telomere length and status, as assessed by quantitative PCR, fluorescence in situ hybridization (FISH), and expression levels of four genes involved in telomere maintenance. Based on the G-banding results, the tumors were divided into two groups, one with a high frequency of tas and one with a low frequency. Clonal aberrations were found to be restricted to the group with a high level of tas, and the same group showed a significantly larger reduction in telomere length in tumor cells compared to peripheral blood cells. Furthermore, 65 out of 66 tas analyzed by FISH were negative for telomeric sequences. The expression levels of TERT, TERF1, TERF2, and POT1 did not correlate with telomere length or the frequency of tas. Thus, the present findings provide strong support for the notion that decreased telomere length is a prerequisite for tas in GCTBs and that the clonal changes occurring in GCTBs are derived from tas.
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| 2. |
- Jin, Yuesheng, et al.
(författare)
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Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:5, s. 510-520
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue angiofibroma is a recently delineated tumor type of unknown cellular origin. Cytogenetic analysis of four cases showed that they shared a t(5;8)(p15;q13). In three of them it was the sole change, underlining its pathogenetic significance. FISH mapping suggested the involvement of the aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2) genes in 5p15 and 8q13, respectively. RT-PCR revealed in-frame AHRR/NCOA2 and NCOA2/AHHR transcripts in all four cases. Interphase FISH on paraffin-embedded tissue from 10 further cases without cytogenetic data showed that three were positive for fusion of AHRR and NCOA2. While AHRR has never been implicated in gene fusions before, NCOA2 is the 3'-partner in fusions with MYST3 and ETV6 in leukemias and with PAX3 and HEY1 in sarcomas. As in the previously described fusion proteins, NCOA2 contributes with its two activation domains to the AHRR/NCOA2 chimera, substituting for the repressor domain of AHRR. Because the amino terminal part of the transcription factor AHRR, responsible for the recognition of xenobiotic response elements in target genes and for heterodimerization, shows extensive homology with the aryl hydrocarbon receptor (AHR), the fusion is predicted to upregulate the AHR/ARNT signaling pathway. Indeed, global gene expression analysis showed upregulation of CYP1A1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors. Apart from providing a diagnostic marker for soft tissue angiofibroma, the results also suggest that this tumor constitutes an interesting model for evaluating the cellular effects of AHR signaling. © 2012 Wiley Periodicals, Inc.
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| 3. |
- Gisselsson Nord, David, et al.
(författare)
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Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:47, s. 20489-20493
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Tidskriftsartikel (refereegranskat)abstract
- One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.
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| 4. |
- Hallor, Karolin Hansén, et al.
(författare)
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Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma
- 2005
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 44:1, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that usually occurs in children and young adults. Only two cases of AFH with genetic rearrangements have been reported previously; both of these had a FUS-ATF1 fusion gene. We have studied an AFH from a 9-year-old boy whose tumor displayed a t(12;22)(q13;q12) as the sole cytogenetic aberration. FISH,RT-PCR, and sequence analyses revealed an EWSR1-ATF1 fusion gene that has previously been reported in clear cell sarcoma (CCS), a soft tissue sarcoma that is morphologically and clinically distinct from AFH. This study thus has demonstrated that the EWSR1-ATF1 chimera represents a fusion gene that can be associated with different tumor types. Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in CCS has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. The AFH, however, did not express the MITF-M transcript, supporting the theory that MITF-M expression in CCS is a reflection of its cellular origin, rather than a consequence of the presence of an EWSR1-ATF1 fusion protein. Activation of the EWSR1-ATF1 oncogene is probably an early step in the transformation process, but the overall gene expression patterns are likely to vary considerably between AFH and CCS, in keeping with their clinicopathologic differences.
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| 5. |
- Jin, Charlotte, et al.
(författare)
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Characterization of chromosome aberrations in salivary gland tumors by FISH, including multicolor COBRA-FISH
- 2001
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 30:2, s. 161-167
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Tidskriftsartikel (refereegranskat)abstract
- Fluorescence in situ hybridization (FISH), including COBRA-FISH, was used to characterize 11 salivary gland tumors that had been investigated by banding analysis. Five cases were pleomorphic adenoma (PA), three were adenoid cystic carcinoma, and one case each was mucoepidermoid carcinoma, carcinoma ex-pleomorphic adenoma (CaPA), and adenocarcinoma. All 11 cases were selected on the basis that they had shown rearrangement of 6q or 9p or had unresolved aberrations after karyotyping. The COBRA-FISH and FISH analyses led to a revised karyotype in all informative cases and made it possible to clarify almost all chromosomal rearrangements occurring in the tumors. Of particular note were the confirmation of the existence of 6q deletions, a common change in salivary gland carcinomas, and the demonstration that a seemingly balanced t(6;9) resulted in del(6q). Other rearrangements that were revealed by FISH included amplification of 12q sequences (MDM2 and CDK4) in one PA. We also investigated the status of the PLAG1 gene in four cases (one PA, one CaPA, one adenoid cystic carcinoma, and one mucoepidermoid carcinoma) with 8q12 rearrangements. Only in the former two cases were the FISH results compatible with intragenic rearrangements. Overall, the results of the study show that, even with good banding quality and in karyotypes of modest complexity, much new information will be gained by supplementing the banding analysis with a multicolor FISH approach, such as COBRA-FISH.
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| 6. |
- Jin, Charlotte, et al.
(författare)
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Cytogenetic abnormalities in 106 oral squamous cell carcinomas
- 2006
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 164:1, s. 44-53
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Tidskriftsartikel (refereegranskat)abstract
- We report karyotypic features of 106 short-term cultured oral squamous cell carcinomas (SCC), 51 new and 55 previously reported cases, with clonal chromosome aberrations. The major cytogenetic findings were as follows: simple karyotypic changes were present in 38 cases (36%) and 68 tumors (64%) displayed complex karyotypes. The most common numerical changes were +7, +8, +9, +16, +18, +20, and -4, -10, -13, -14, -18, -19, -21, -22, and -Y. Structural rearrangements frequently (43% of the breaks) affected the centromeric regions, resulting in the formation of isochromosomes and whole-arm translocations. Among the recurrent structural aberrations identified, the most common were i(1q), i(3q), i(5p), i(8q), del(16)(q22), and hsr. With the exception of chromosomal band 11q13, which was involved in 25 tumors, only centromeric or near-centromeric bands were commonly involved: 3p11 approximately q11 (59 cases), 8p11 approximately q11 (57), 1p11 approximately q11 (48), 13p11 approximately q11 (46), 5p11 approximately q11 (41), 14p11 approximately q11 (41), and 15p11 approximately q11 (37). Losses of genetic material dominated over gains. The most frequent imbalances included loss of 2q33 approximately qter, 3p, 4p, 6q, 8p, 10p, 11q, 13p, 14p, and 15p, and chromosomes 18, 21, 22, and Y, and gain of chromosomes 7 and 20, 8q, and 11q13. No major karyotypic differences could be discerned between the present series of oral SCC and a previously reported series of laryngeal SCC, indicating that common genetic pathways are involved in the initiation and progression of SCC irrespective of site of origin.
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| 7. |
- Jin, Charlotte, et al.
(författare)
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Increased sensitivity to bleomycin in upper aerodigestive tract mucosa of head and neck squamous cell carcinoma patients.
- 2008
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Ingår i: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. - : Elsevier BV. - 1383-5718. ; 652, s. 30-37
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies on lymphocytes have suggested that patients with head and neck squamous cell carcinoma (HNSCC) have an increased susceptibility for chromosomal damage induced by bleomycin, a known radiomimetic mutagen. However, it has so far not been possible to study whether this genetic instability is present also in the epithelial component of the upper aerodigestive tract mucosa, the tissue from which HNSCC originates. In the present study, we have successfully cultured epithelial cells and fibroblasts isolated from non-neoplastic mucosa samples of 30 HNSCC patients and 56 controls. All cell cultures were exposed to bleomycin and chromosome instability was assessed by analysis of chromosome breakage in cells harvested after 2h of exposure and subsequent removal of bleomycin. Furthermore, the status of the fragile histidine triad gene (FHIT) in chromosome band 3p14.2 was studied by fluorescence in situ hybridization (FISH) in epithelial cells that had been cultured after removal of bleomycin. Chromosomal damage, in the form of chromosomal breaks and gaps, was seen in all cell cultures harvested 2h after exposure to bleomycin. In epithelial cells, the frequency of chromosome breakage was significantly higher among HNSCC patients than among controls [mean breaks per cell (b/c) 1.02 vs. 0.77, p=0.02]. When subdivided according to smoking status, age, and sex, a significantly higher frequency of chromosome breakage was still found in HNSCC patients (smokers, p=0.01, age
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| 8. |
- Jin, Charlotte, et al.
(författare)
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Karyotypic heterogeneity and clonal evolution in squamous cell carcinomas of the head and neck.
- 2002
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 132:2, s. 85-96
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck squamous cell carcinomas (HNSCC) are often characterized by complex karyotypic changes, and a substantial proportion of the reported tumors have shown intratumor heterogeneity in the form of cytogenetically related (40%) or unrelated clones (20%). In order to study intratumor heterogeneity and to distinguish the temporal order of chromosome rearrangements in these tumors, two or more samples from different areas of the same tumor were separately examined in 19 HNSCC, yielding karyotypes from a total of 42 tumor samples. Intrasample heterogeneity was observed in 16 samples. Two samples displayed both related and unrelated multiple clones, four samples showed only multiple unrelated clones, and the remaining 10 samples had only related subclones. Intersample heterogeneity was detected in all but one tumor. Five tumors showed both cytogenetically related and unrelated multiple clones, 11 were found to have only related subclones, and the remaining two tumors showed only unrelated clones. Clonal evolution could be assessed in 13 tumors. A comparison of chromosome imbalances in different subclones from these tumors suggests that partial or entire loss of 3p, 8p, 9p, and 18q and gain of genetic material from 3q and 8q are likely to be early genetic events. In contrast, loss of 1q, 6p, 7q, and chromosome 10, as well as gain of chromosome arms 5p and 7p, are most probably later genetic events. One of the examined tumors contained two highly complex clones that were cytogenetically unrelated, indicating that this tumor had a multicellular origin.
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| 9. |
- Jin, Charlotte, et al.
(författare)
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Molecular cytogenetic characterization of the 11q13 amplicon in head and neck squamous cell carcinoma.
- 2006
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 115:2, s. 99-106
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Tidskriftsartikel (refereegranskat)abstract
- Amplification of 11q13 DNA sequences and overexpression of CCND1 are common findings in head and neck squamous cell carcinoma (HNSCC), identified in about 30% of the cases. However, little is known about initiation of the amplification and the organization of the amplicon. In order to study the structure of the amplicon in more detail and to learn more about the mechanisms involved in its initiation, prometaphase, metaphase, and anaphase fluorescence in situ hybridization (FISH) with 40 BAC clones spanning a 16-Mb region in chromosome bands 11q12.2 to 11q13.5 was performed in nine HNSCC cell lines with homogeneously staining regions. FISH analysis showed that the size of the amplicon varied among the nine cell lines, the smallest being 2.12 Mb and the largest 8.97 Mb. The smallest overlapping region of amplification was approximately 1.61 Mb, covering the region from BAC 729E14 to BAC 102B19. This region contained several genes previously shown to be amplified and overexpressed in HNSCC, including CCDN1, CTTN, SHANK2, and ORAOV1. The cell lines were also used to study the internal structure of the amplicon. Various patterns of amplified DNA sequences within the amplicon were found among the nine cell lines. Even within the same cell line, different amplicon structures could be found in different cell populations, indicating that the mechanisms involved in the development of the amplicons in HNSCC were more complex than previously assumed. The frequent finding of inverted repeats within the amplicons, however, suggests that breakage-fusion-bridge cycles are important in the initiation, but the fact that such repeats constituted only small parts of the amplicons indicate that they are further rearranged during tumor progression. Copyright (c) 2006 S. Karger AG, Basel.
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| 10. |
- Jin, Yuesheng, et al.
(författare)
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Cyclin D1 amplification in chromosomal band 11q13 is associated with overrepresentation of 3q21-q29 in head and neck carcinomas.
- 2002
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 98:3, s. 475-479
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Tidskriftsartikel (refereegranskat)abstract
- Eight cytogenetically characterized head and neck squamous cell carcinomas (HNSCCs) with CCND1 amplification in the form of a homogeneously staining region (hsr) in 11q13 were studied by COBRA FISH and FISH with specific probes to identify and characterize chromosomal segments added to the derivative chromosomes 11. In 4 of the tumors, it could be recognized that the material added was derived from the long arm of chromosome 3. The rearrangements were interpreted as der(11)hsr(11)(q13)t(3;11)(q21;q13) in 3 cases and as der(11)hsr(11)(q13)t(3;11)(q14;q13) in 1 case. In the other 4 cases, material from chromosomes 1, 16, or 19 was added to the derivative chromosomes 11. By further FISH analysis with 14 YAC clones spanning 3q13-q21 in the 4 tumors with der(11)hsr(11)t(3;11), it could be shown that they had different breakpoints at the molecular level, excluding the possibility that a particular gene was rearranged by the translocations. More surprisingly, gain of the 3q21-q29 segment was found in all 8 tumors with hsr in 11q13 and loss of 3p was seen in 7 of the tumors. These findings strongly indicate a synergistic effect of CCND1 amplification, loss of distal 11q, 3q gain and 3p deletion in HNSCC development and also suggests a mechanistic link between intrachromosomal amplification at 11q13 and recombination with distal 3q.
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