| 1. |
- Dictor, Michael, et al.
(författare)
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Abnormal cell cycle regulation in malignancy
- 1999
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Ingår i: American Journal of Clinical Pathology. - 0002-9173. ; 112:1 Suppl 1, s. 40-52
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Forskningsöversikt (refereegranskat)abstract
- The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), and mitosis (M), after which the cell may differentiate or enter the resting state (G0). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events, involving protein kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors, that ultimately impinge on the activity of transcription factors. Unreplicated or damaged DNA blocks the progression of the cell cycle at checkpoints, including a late G1 checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be considered proto-oncogenes or tumor suppressor genes, and point mutations, amplifications, deletions, or rearrangements involving their loci, particularly those in the "RB pathway," are associated with various tumors. A number of molecular techniques may be used to detect genomic alterations or posttranscriptional modifications, but immunohistochemistry remains the most common method to determine expression levels of a regulatory protein. Multivariate analysis of the usefulness in prognosis has been applied most often for the general proliferation antigen Ki-67.
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| 2. |
- Gisselsson Nord, David, et al.
(författare)
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Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region. Metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics
- 1999
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Ingår i: American Journal of Pathology. - 1525-2191. ; 155:1, s. 61-66
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Tidskriftsartikel (refereegranskat)abstract
- Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. In this study, the chromosome 11 changes in five hibernomas were analyzed in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in four cases also in the ostensibly normal homologues, resulting in homozygous loss of several loci. Among these, the gene for multiple endocrine neoplasia type I (MEN1) was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all five cases, adding to previous evidence for a second tumor suppressor locus in 11q13.
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| 3. |
- Gisselsson Nord, David, et al.
(författare)
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The structure and dynamics of ring chromosomes in human neoplastic and non-neoplastic cells
- 1999
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 104:4, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- Acquired ring chromosomes have been found in most types of human neoplasia, with a frequency approaching 10% in malignant mesenchymal tumours. In this study, the composition and dynamics of ring chromosomes were analysed in eight cases of acute myelogenous leukaemia, 17 solid tumours, and five cases with constitutional rings. Chromosomal banding and fluorescence in situ hybridisation were performed to determine the content and the structural heterogeneity of the rings. Telomeric repeats were detected using peptide nucleic acid probes or primed in situ labelling, whereas centromeric activity was evaluated by detection of kinetochore proteins. Mitotic instability was assessed by the frequency of anaphase bridges. The results suggest that human ring chromosomes can be structurally and functionally divided into two categories. In the first of these, size variation is minimal and rearrangement at cell division is uncommon. The majority of such rings contain subtelomeric sequences. Constitutional ring chromosomes and most rings in leukaemias belong to this group, whereas only a few mesenchymal tumours exhibit rings of this type. The second category consists of rings with amplified sequences, primarily from chromosome 12, characteristically occurring in atypical lipomatous tumours and other subtypes of low or borderline malignant mesenchymal neoplasms. Variation in size and number is extensive, and breakage-fusion-bridge events occur at a high frequency. Abnormalities in pericentromeric sequences are common and, in some cases, kinetochores assemble in the absence of alphoid DNA. We conclude that it is not only the ring structure per se or the neoplastic nature of the host cell that determines ring instability, but probably also the functional role of the genes carried in the ring.
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| 4. |
- Gisselsson Nord, David, et al.
(författare)
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Unique cytological features and chromosome aberrations in chondroid lipoma: a case report based on fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and molecular cytogenetics
- 1999
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Ingår i: American Journal of Surgical Pathology. - 1532-0979. ; 23:10, s. 1300-1300
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Tidskriftsartikel (refereegranskat)abstract
- Chondroid lipoma is a rare, benign tumor that may mimic soft-tissue sarcoma clinically. Its histopathologic features may resemble hibernoma, myxoid liposarcoma, myxoid chondrosarcoma, and other lipomatous or chondroid neoplasms. In this study, a chondroid lipoma was analyzed by fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and metaphase fluorescence in situ hybridization. The results demonstrate that chondroid lipoma exhibits a characteristic pattern by fine-needle aspiration cytology, including a mixture of benign adipose tissue with lipoblastlike cells, and chondroblastlike cells with a fibrochondroid matrix. Cytogenetically, a three-way rearrangement between chromosomes 1, 2, and 5 was found, together with an 11;16 translocation with a breakpoint in 11q13, approximately 1 Mb proximal to the MEN1 region shown to be rearranged frequently in hibernoma. The presence of a karyotype of low complexity, but without any of the genetic aberrations characteristic for other types of soft-tissue tumors, indicate that chondroid lipoma develops along a unique pathogenetic pathway.
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| 5. |
- Gisselsson Nord, David, et al.
(författare)
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Variable stability of chromosomes containing amplified alpha-satellite sequences in human mesenchymal tumours
- 1999
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Ingår i: Chromosoma. - : Springer Science and Business Media LLC. - 0009-5915 .- 1432-0886. ; 108:5, s. 271-277
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-satellite sequences are found in the centromeric region of all human chromosomes and have been implicated in centromeric function. We describe the structure and behaviour of chromosomes containing amplified human alphoid DNA from chromosome 12, in an osteosarcoma cell line (OSA) and an atypical lipomatous tumour (ALT). In OSA, the amplified material was detected in one large marker chromosome, whereas in ALT amplified sequences were observed in chromosomes of variable number and appearance. The marker in OSA was mitotically stable, but those in ALT exhibited a high degree of mitotic instability, forming bridges at anaphase and chromatin strings between interphase nuclei. The amplified alpha-satellite arrays reacted positively with human anti-centromeric antiserum and anti-centromere protein B antibodies in both tumours. Centromere protein C, previously shown to be present only in functional kinetochores, was invariably detected at the constriction of the marker in OSA, while one-fifth of markers in ALT appeared to exhibit additional centromere protein C-positive regions outside the primary constriction, indicating that the observed chromosomal instability in ALT might, at least in part, be a consequence of the occasional formation of more than one functional kinetochore. In OSA the alphoid DNA was coamplified with unique sequences from central 12q and the amplified material was C-band negative but in ALT amplified material from central 12q as well as sequences from proximal 12p were detected, resulting in C-band-positive areas. A propensity for additional kinetochore formation might thus be associated with the coamplification of alphoid DNA and pericentromeric sequences from chromosome 12.
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| 6. |
- Kullendorff, Carl-Magnus, et al.
(författare)
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Cytogenetic aberrations in Ewing sarcoma: are secondary changes associated with clinical outcome?
- 1999
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Ingår i: Medical and Pediatric Oncology. - 1096-911X. ; 32:2, s. 79-83
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ewing sarcoma is associated with a nonrandom pattern of primary and secondary chromosomal aberrations. Whereas the finding of rearrangements of chromosome 22, usually in the form of a balanced translocation t(11;22)(q24;q12), is important diagnostically, nothing is known about the potential prognostic impact of the secondary chromosomal aberrations. PROCEDURE: During a 1 3-year-period, short-term cultured tumor samples from 21 children and young adults with Ewing sarcoma were cytogenetically analyzed successfully. RESULTS: Clonal chromosome aberrations were detected in 18 patients, 17 of whom had the characteristic t(11;22)(q24;q12) or variants thereof. The most frequent secondary change was +8, followed by +12, +2, +5, +9, +15, and gain of material from the long and short arms of chromosome 1. The only recurrent secondary change that was restricted to tumors from the ten patients that were dead at latest follow-up was gain of 1q material. Furthermore, all three patients with tumors with chromosome numbers over 50 had died, and the only patient with a tumor karyotype lacking chromosome 22 rearrangement was alive without evidence of disease. CONCLUSIONS: These data and previously published results indicate that the karyotypic pattern not only may be of diagnostic significance but also may be important prognostically.
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| 7. |
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| 8. |
- Mitelman, Felix, et al.
(författare)
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A breakpoint map of recurrent chromosomal rearrangements in human neoplasia
- 1997
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 15:4, s. 417-474
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Tidskriftsartikel (refereegranskat)abstract
- Cytogenetic studies over the past few decades have revealed clonal chromosomal aberrations in almost 27,000 human neoplasms. Many of these neoplasia-associated chromosomal abnormalities have been characterised at the molecular level, revealing previously unknown genes that are closely associated with the tumorigenic process. Information on chromosome changes in neoplasia is growing rapidly, making it difficult to identify all recurrent chromosomal aberrations. We have developed a computer program to ascertain, for the first time, all recurrent structural abnormalities in all haematological malignancies and solid tumours published up to June 1996. Out of 26,523 cases, a total of 215 balanced and 1,588 unbalanced recurrent aberrations were identified among 75 different neoplastic disorders. Our compilation of all recurrent balanced and unbalanced neoplasia-associated rearrangements should help in directing future efforts aimed at identifying the molecular mechanisms involved in tumorigenesis.
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| 9. |
- Persson, Karin, et al.
(författare)
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Chromosomal aberrations in breast cancer: a comparison between cytogenetics and comparative genomic hybridization
- 1999
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 25:2, s. 115-122
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of chromosomal imbalances in solid tumors using comparative genetic hybridization (CGH) has gained much attention. A survey of the literature suggests that CGH is more sensitive in detecting copy number aberrations than is karyotyping, although careful comparisons between CGH and cytogenetics have not been performed. Here, we compared cytogenetics and CGH in 29 invasive breast cancers after converting the karyotypes into net copy number gains and losses. We found 15 tumors (56%) with a significant agreement between the two methods and 12 tumors (44%) where the methods were in disagreement (two cases failed CGH analysis). Interestingly, in 13 of the 15 tumors where the two methods were concordant, there was also a strong correlation between chromosome index and DNA index by flow cytometry. In the opposite situation, i.e., when chromosome and DNA indices were not matching, there was disagreement between cytogenetics and CGH in 10 of the 12 tumors. Of the discordant cases, all except one had a "simple" abnormal karyotype. Unresolved chromosomal aberrations (marker chromosomes, homogeneously staining regions, double minutes) could not completely explain the differences between CGH and karyotyping. A likely explanation for the discrepancies is that the methods analyzed different cell populations. Gains and losses found by CGH represented the predominant (often aneuploid) clone, whereas the abnormal, near-diploid karyotypes represented minor cell clone(s), which, for unknown reasons, had a growth advantage in vitro.
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| 10. |
- Åkervall, Jan, et al.
(författare)
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Complex karyotypes in flow cytometrically DNA-diploid squamous cell carcinomas of the head and neck
- 1998
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Ingår i: British Journal of Cancer. - 1532-1827. ; 77:7, s. 1082-1088
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Tidskriftsartikel (refereegranskat)abstract
- In squamous cell carcinoma of the head and neck (SCCHN), DNA ploidy as determined by flow cytometry (FCM) has been found to yield prognostic information but only for tumours at oral sites. Cytogenetic findings have indicated complex karyotype to be a correlate of poor clinical outcome. In the present study, 73 SCCHN were investigated with the two techniques. Aneuploid cell populations were identified in 49 (67%) cases by FCM but in only 21 (29%) cases by cytogenetic analysis. The chromosome index (CI), calculated as the mean chromosome number divided by 46, was compared with the respective DNA index (DI) obtained by FCM in 15 tumours, non-diploid according to both techniques, DI being systematically 12% higher than CI in this subgroup. Eight (33%) of the 24 tumours diploid according to FCM had complex karyotypes, three of the tumours being cytogenetically hypodiploid, three diploid and two non-diploid. The findings in the present study may partly explain the low prognostic value of ploidy status as assessed by FCM that has been observed in SCCHN. In addition, we conclude that FCM yields information of the genetic changes that is too unspecific, and that cytogenetic analysis shows a high rate of unsuccessful investigations, thus diminishing the value of the two methods as prognostic factors in SCCHN.
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