| 1. |
- 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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| 2. |
- Höglund, Mattias, et al.
(författare)
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Multivariate analyses of genomic imbalances in solid tumors reveal distinct and converging pathways of karyotypic evolution
- 2001
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 31:2, s. 156-171
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Tidskriftsartikel (refereegranskat)abstract
- A total of 3,016 malignant solid tumors (kidney, colorectal, breast, head and neck, ovarian, and lung carcinomas, neuroglial tumors, malignant melanoma, and testicular germ cell tumors) were selected for statistical analyses regarding karyotypic evolution. Genomic imbalances, i.e., net gains and losses, present in more than 5% of each tumor type were identified. Individual tumors were then classified with respect to absence or presence of these imbalances. To analyze for possible patterns of correlated imbalances, principal component analyses (PCA) were performed. Furthermore, algorithms were developed to analyze the temporal order of the imbalances, as well as the possible selection for early or late appearance in the karyotypic evolution. By analyzing the temporal order of imbalances common to many tumor types, a general order for nine of these emerged, namely, +7, -3p, -6q, -1p, -8p, -17p, -9p, -18, and -22. The distributions of the number of imbalances per case revealed a geometrical distribution, ranging from one to nine imbalances per tumor, in the majority of the tumor types. In tumor types in which cases with a high number of imbalances per case were frequent, notably head and neck, ovarian, and lung carcinomas, the overall distributions were bimodal, indicating the presence of two modes of chromosome evolution. By combining data from the PCA with the temporal analyses, it was possible to identify karyotypic pathways. It was found that the majority of the tumor types displayed more than one cytogenetic route, but, as the karyotypic evolution continued, these converged to a common pathway.
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| 3. |
- JOHANSSON, BERTIL, et al.
(författare)
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Breakprone chromosome bands in fibroblasts from patients with non‐Hodgkin's lymphoma do not coincide with bands involved in primary rearrangements in non‐Hodgkin's lymphomas
- 1988
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Ingår i: Hereditas. - : Springer Science and Business Media LLC. - 0018-0661. ; 109:1, s. 131-137
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of breakpoints in structural chromosome aberrations (chromatid and chromosome gaps, breaks, and exchanges) was studied in skin fibroblasts from 35 untreated patients with non‐Hodgkin's lymphoma (NHL) and 39 controls. A total of 227 aberrations in the NHL group and 260 in the control group could be assigned to specific chromosome bands. The distribution of breakpoints was nonrandom in both groups (p<0.001), with excessive breakage in 17 bands among the NHL patients and in 21 among the controls. Two of the hot spots in the NHL group (6q21,14q24) and three in the control group (2q33,6q21, 6q25) coincided with the 60 chromosome bands that are targets for primary chromosome abnormalities in NHL. We conclude that the chromosome bands involved in primary structural abnormalities in lymphoma cells are not constitutionally breakprone in NHL patients.
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| 4. |
- Johansson, Bertil, et al.
(författare)
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Most gene fusions in cancer are stochastic events
- 2019
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 58:9, s. 607-611
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated gene fusions resulting in chimeric proteins or aberrant expression of one or both partner genes are pathogenetically and clinically important in several hematologic malignancies and solid tumors. Since the advent of different types of massively parallel sequencing (MPS), the number of identified gene fusions has increased dramatically, prompting the question whether they all have a biologic impact. By ascertaining the chromosomal locations of 8934 genes involved in 10 861 gene fusions reported in the literature, we here show that there is a highly significant association between gene content of chromosomes and chromosome bands and number of genes involved in fusions. This strongly suggests that a clear majority of gene fusions detected by MPS are stochastic events associated with the number of genes available to participate in fusions and that most reported gene fusions are passengers without any pathogenetic importance.
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| 5. |
- JOHANSSON, BERTIL, et al.
(författare)
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Normal frequency of structural chromosome aberrations in fibroblasts from patients with non‐Hodgkin's lymphoma
- 1988
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Ingår i: Hereditas. - : Springer Science and Business Media LLC. - 0018-0661. ; 109:2, s. 277-280
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of chromosome aberrations, i.e., chromatid and chromosome gaps, breaks, and exchanges, was studied in cultured skin fibroblasts from 25 untreated patients with non‐Hodgkin's lymphoma (NHL) and 26 controls. The mean frequencies of aberrant cells, and gap, break, and gap+break events per 100 metaphases were 4.2, 1.9, 2.8, and 4.7 in the NHL group, and 5.1, 2.6, 3.2, and 5.8 in the control group. None of these parameters differed significantly between the groups, indicating that constitutional chromosomal instability is not related to the development of NHL. In the total material there was a significant (P<0.05) increase with age in the number of aberrant cells.
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| 6. |
- Johansson, Bertil, et al.
(författare)
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Remarkably long survival of a patient with Ph1-positive chronic myeloid leukemia and 5' bcr rearrangement
- 1990
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Ingår i: Leukemia. - 1476-5551. ; 4:6, s. 448-449
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) was diagnosed in a 19-year-old man in 1961, and the disease remained in chronic phase, with occasional exacerbations, for 27 years. In 1976, when the first cytogenetic analysis was performed, t(9;22)(q34;q11) was found as the sole abnormality in all mitoses. During accelerated phase in 1988, a second cytogenetic investigation showed the karyotype 45,XY,t(9;22)(q34;q11),-15,-17,+der(15) t(15;17)(p13;q11). Molecular analysis revealed a rearrangement in the 5' end of the major breakpoint cluster region (M-bcr). With the case presented here, sublocalization of the bcr breakpoint has now been undertaken in altogether five CML patients with extremely long survival. It is noteworthy that in all these cases the chromosome 22 breakpoint was located in the 5' region of the M-bcr.
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| 7. |
- Mandahl, Nils, et al.
(författare)
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Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:6, s. 536-544
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Tidskriftsartikel (refereegranskat)abstract
- The chromosome number of human tumors varies widely, from near-haploidy to more than decaploidy. Overt hyperhaploid (24-34 chromosomes) tumors constitute a small minority (0.2-0.3% of cytogenetically investigated lesions), but occur in many different disease entities. In these karyotypes, most chromosomes are present in one copy; one or a few chromosomes are disomic. Published reports on 141 strictly hyperhaploid tumors, supplemented with nine previously unpublished cases, were used for evaluating the pattern of disomic chromosomes. Only one tumor type, acute lymphoblastic leukemia (ALL), was sufficiently common (n = 75) to allow proper evaluation; other neoplasms were lumped together in as reasonably logical groups as possible, including 10 myeloid leukemias (ML), nine plasma cell neoplasms (PCN), 13 chondrosarcomas (CS), 11 soft tissue tumors (STT), nine adeno- or squamous cell carcinomas (ASC), and eight tumors of the nervous system (TNS); the remaining 15 tumors could not be grouped. It was evident that the pattern of disomies is nonrandom. Moreover, unique signatures for each tumor group were detected. Among ALL, most disomies were independent of age and gender, except for disomy 10, which was overrepresented in females. Chromosome 21 was invariably disomic, whereas chromosome 17 was always monosomic. The most frequent disomies were two gonosomes in ML, chromosomes 7, 9, 11, 3, 18, and 19 in PCN, 7, 5, 20, 19, and 21 in CS, 20 in STT, 7 in ASC, and 1, 7, and 9 in TNS. Chromosome 1 was often partially disomic, due to unbalanced structural rearrangements, with segment 1q21-31 in common. Doubling of the hyperhaploid clone was found in at least one-third of the cases, apart from in ML where only one of 10 cases showed chromosome doubling. The present findings indicate that retention of disomy for some chromosomes is pathogenetically important and that the chromosome(s) maintained in two copies is related to cell type or histological context. © 2012 Wiley Periodicals, Inc.
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| 8. |
- Mitelman, Felix, et al.
(författare)
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Cancer chromosome breakpoints cluster in gene-rich genomic regions
- 2019
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 58:3, s. 149-154
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22 344 different clonal structural chromosome abnormalities identified in the karyotypes of 49 626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P < 0.0001) with gene content within the affected chromosomal bands. This association also remains highly significant in separate analyses of recurrent and nonrecurrent chromosome abnormalities as well as of specific subtypes of cancer (P < 0.0001 for all comparisons). In contrast, the impact of band length was negligible. The breakpoint distribution is thus not stochastic—gene-rich regions are preferentially affected. Several genomic features relating to transcription, replication, and chromatin organization have been found to enhance chromosome breakage frequencies; this indicates that gene-rich regions may be more break-prone. The salient finding in the present study is that a substantial fraction of all structural chromosome abnormalities, not only those specifically associated with certain tumor types, may affect genes that are pathogenetically important. If this interpretation is correct, then the prevailing view that the great majority of cancer chromosome aberrations is cytogenetic noise can be seriously questioned.
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| 9. |
- Panagopoulos, Ioannis, et al.
(författare)
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Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22)
- 1994
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 11:4, s. 256-262
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Tidskriftsartikel (refereegranskat)abstract
- It has been shown that the gene ERG in 21q22 is rearranged in the the t(16;21)(p11;q22) associated with acute myeloid leukemia (AML). ERG is a member of the ETS gene family and is fused with EWS in a subset of Ewing's sarcomas. EWS in 22q12 has a very high homology with FUS (also called TLS) in 16p11; the latter gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma. To investigate whether FUS is involved in the t(16;21) of AML, we used the Southern blot technique and polymerase chain reaction (PCR) to examine the bone marrow of a 3-year-old boy with a t(16;21)(p11;q22)-positive AML. Hybridization of Southern blot filters containing digested DNA with probes for FUS and ERG showed both germline and aberrant fragments. Using specific primers for the 5 part of FUS and the 3 part of ERG, we amplified a 4.4 kb genomic FUS/ERG DNA fragment from the leukemic sample. In a second PCR experiment, in which we used primers upstream of the 5 part of ERG and downstream of the 3 part of FUS, a 5.6 kb fragment was amplified. Blotting and hybridization with specific probes for FUS and ERG revealed that the amplified fragments consisted of FUS/ERG and ERG/FUS hybrid DNA. Both PCR fragments, when used as probes, detected germline ERG and FUS as well as aberrant fragments on Southern blot filters. The results suggest that the t(16;21) in AML leads to rearrangement and fusion of the FUS and ERG genes. This is the first example in which two genes, each known to recombine with other genes in different solid tumor types (FUS in myxoid liposarcoma and ERG in Ewing's sarcoma), are fused in a hematologic malignancy.
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