| 61. |
- 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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| 62. |
- 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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| 63. |
- 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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| 64. |
- Johnsson, Anna, et al.
(författare)
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Unstable translocation (8;22) in a case of giant cell reparative granuloma.
- 2007
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 177:1, s. 59-63
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Tidskriftsartikel (refereegranskat)abstract
- Giant cell reparative granuloma (GCRG) is an uncommon lesion most often affecting the jaw but also the small bones of the hands and feet. GCRG overlaps clinically and radiographically with other giant cell-rich tumors such as giant cell tumor of bone (GCTB) and aneurysmal bone cyst (ABC). In the only case of a cytogenetically investigated GCRG reported previously, a balanced translocation involving chromosomes 4 and X was found. In the present study, chromosome banding and fluorescence in situ hybridization (FISH) analyses were used to characterize the primary lesion and local recurrence of a GCRG in the thumb and skin biopsy of a 45-year-old woman. The skin showed a normal karyotype. Various forms of a dic(8;22) containing 8q, 22q, and smaller or larger parts of 8p were found in both GCRG samples. In addition, ring chromosomes, most often composed of chromosome I I material, and telomeric associations were found. The latter aberrations were more frequent in the primary lesion. Normal FISH signals were seen when using probes capable of detecting USP6 rearrangernents. The variant 8;22 aberrations were interpreted to originate from an unstable dic(8;22)(p23;p11) that gradually evolved into a functionally monocentric chromosome in the dominating subset of cell populations. We conclude that our case of GCRG shared several cytogenetic characteristics with GCTB but none with ABC. (c) 2007 Elsevier Inc. All rights reserved.
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| 65. |
- Joseph, Christine G., et al.
(författare)
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Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 53:1, s. 15-24
-
Tidskriftsartikel (refereegranskat)abstract
- Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide-level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis. (c) 2013 Wiley Periodicals, Inc.
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| 66. |
- Karlsson, Christine, et al.
(författare)
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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.
- 2007
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 33:4, s. 440-454
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.
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| 67. |
- Kaur, S., et al.
(författare)
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Gene copy number changes in dermatofibrosarcoma protuberans - a fine-resolution study using array comparative genomic hybridization
- 2006
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 115:3-4, s. 283-288
-
Tidskriftsartikel (refereegranskat)abstract
- Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing, low-grade dermal tumor. Cytogenetic and FISH studies have revealed that the chromosomal rearrangements characteristic of DFSP tumors involve both translocations and the formation of a supernumerary ring derived from chromosomes 17 and 22. The t(17;22) (q22;q13.1) translocation generates a gene fusion between COL1A1 and PDGFB, which serves as a diagnostic marker of DFSP. In the present study we performed array-CGH (aCGH) analysis on ten DFSP tumors. The COL1A1 region at 17q was gained in 71% (5/7) of the samples and the PDGFB region at 22q was gained in 43% (3/7) of the individual samples. In addition to the 17q and 22q gains, altogether 17 minimal common regions of gain and one region of loss were detected.
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| 68. |
- Killela, Patrick J., et al.
(författare)
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TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:15, s. 6021-6026
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (>= 15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
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| 69. |
- Kjellstrand, Per, et al.
(författare)
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Effects of continuous Trichloroethylene inhalation on different strains of mice
- 1983
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Ingår i: Acta Pharmacologica et Toxicologica. - : Wiley. - 0001-6683. ; 53:5, s. 369-374
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Tidskriftsartikel (refereegranskat)abstract
- Seven different strains of mice (wild, C57BL, DBA, B6CBA, A/sn, NZB and NMRI) were continuously exposed to 150 ppm trichloroethylene (TCE) during 30 days. After exposure all strains showed large increases in liver weight, while changes in kidney and spleen weights were small. Plasma butyrylcholinesterase (BuChE) activity increased in males of all strains and in females of strains A/sn and NZB. The increase in the females was less than that of the corresponding males. We concluded that there are moderate, but in some cases, significant differences in TCE sensitivity between different mouse strains. The differences observed between sexes emphasizes the importance of specifying sex as well as strain when reporting on toxic effects.
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| 70. |
- Kolberg, Matthias, et al.
(författare)
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Protein expression of BIRC5, TK1, and TOP2A in malignant peripheral nerve sheath tumours - A prognostic test after surgical resection.
- 2015
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 9:6, s. 1129-1139
-
Tidskriftsartikel (refereegranskat)abstract
- No consensus treatment regime exists beyond surgery for malignant peripheral nerve sheath tumours (MPNST), and the purpose of the present study was to find new approaches to stratify patients with good and poor prognosis and to better guide therapeutic intervention for this aggressive soft tissue cancer. From a total of 67 MPNSTs from Scandinavian patients with and without neurofibromatosis type 1, 30 MPNSTs were investigated by genome-wide RNA expression profiling and 63 MPNSTs by immunohistochemical (IHC) analysis, and selected genes were submitted to analyses of disease-specific survival. The potential drug target genes survivin (BIRC5), thymidine kinase 1 (TK1), and topoisomerase 2-alpha (TOP2A), all encoded on chromosome arm 17q, were up-regulated in MPNST as compared to benign neurofibromas. Each of them was found to be independent prognostic markers on the gene expression level, as well as on the protein level. A prognostic profile was identified by combining the nuclear expression scores of the three proteins. For patients with completely resected tumours only 15% in the high risk group were alive after two years, as compared to 78% in the low risk group. In conclusion, we found a novel protein expression profile which identifies MPNST patients with inferior prognosis even after assumed curative surgery. The tested proteins are drug targets; therefore the expression profile may provide predictive information guiding the design of future clinical trials. Importantly, as the effect is seen on the protein level using IHC, the biomarker panel can be readily implemented in routine clinical testing.
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