| 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. |
- Johansson, Bertil, et al.
(författare)
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Clinical and biological importance of cytogenetic abnormalities in childhood and adult acute lymphoblastic leukemia
- 2004
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 36:7, s. 492-503
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Forskningsöversikt (refereegranskat)abstract
- Among the approximately 7,000 cytogenetically abnormal childhood and adult B- and T-lineage acute lymphoblastic leukemias (ALL) published to date, numerous recurring chromosomal aberrations and abnormality patterns have been identified, and it has been clearly shown that the cytogenetic features often correlate closely with specific morphologic, immunophenotypic, and clinical parameters. Thus, karyotypic investigations are now routinely performed for diagnostic and prognostic purposes in ALL, with the chromosomal abnormalities/cytogenetic patterns playing a major role for proper risk assessment and choice of treatment. At the same time, the cytogenetic analyses have resulted in the identification of more than 70 different genes, located at the breakpoints of ALL-associated structural chromosomal abnormalities, that are causally implicated in the leukemogenic process. Hence, the genetic studies have also improved our understanding of the mechanisms of leukemogenesis. However, the almost staggering amount of cytogenetic information presently available has made it increasingly difficult to obtain a general overview of the clinical and biological importance of karyotypic patterns in ALL. Here, we summarize and review the cytogenetic features of childhood and adult ALL, with emphasis on their molecular genetic consequences and their clinical impact.
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| 3. |
- Mertens, Fredrik, et al.
(författare)
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Evolving techniques for gene fusion detection in soft tissue tumours.
- 2014
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Ingår i: Histopathology. - : Wiley. - 0309-0167. ; 64:1, s. 151-162
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Forskningsöversikt (refereegranskat)abstract
- Chromosomal rearrangements resulting in the fusion of coding parts from two genes or in the exchange of regulatory sequences are present in approximately 20% of all human neoplasms. More than 1000 such gene fusions have now been described, with close to 100 of them in soft tissue tumours. Although little is still known about the functional outcome of many of these gene fusions, it is well established that most of them have a major impact on tumorigenesis. Furthermore, the strong association between type of gene fusion and morphological subtype makes them highly useful diagnostic markers. Until recently, the vast majority of gene fusions were identified through molecular cytogenetic characterization of rearrangements detected at chromosome banding analysis, followed by use of the reverse transcriptase-polymerase chain reaction (RT-PCR) and Sanger sequencing. With the advent of next-generation sequencing (NGS) technologies, notably of whole transcriptomes or all poly-A(+) mRNA molecules, the possibility of detecting new gene fusions has increased dramatically. Already, a large number of novel gene fusions have been identified through NGS approaches and it can be predicted that these technologies soon will become standard diagnostic clinical tools.
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| 4. |
- Mertens, Fredrik, et al.
(författare)
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Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes.
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 55:4, s. 291-310
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Forskningsöversikt (refereegranskat)abstract
- Gene fusions have been described in approximately one-third of soft tissue tumors (STT); of the 142 different fusions that have been reported, more than half are recurrent in the same histologic subtype. These gene fusions constitute pivotal driver mutations, and detailed studies of their cellular effects have provided important knowledge about pathogenetic mechanisms in STT. Furthermore, most fusions are strongly associated with a particular histotype, serving as ideal molecular diagnostic markers. In recent years, it has also become apparent that some chimeric proteins, directly or indirectly, constitute excellent treatment targets, making the detection of gene fusions in STT ever more important. Indeed, pharmacological treatment of STT displaying fusions that activate protein kinases, such as ALK and ROS1, or growth factors, such as PDGFB, is already in clinical use. However, the vast majority (52/78) of recurrent gene fusions create structurally altered and/or deregulated transcription factors, and a small but growing subset develops through rearranged chromatin regulators. The present review provides an overview of the spectrum of currently recognized gene fusions in STT, and, on the basis of the protein class involved, the mechanisms by which they exert their oncogenic effect are discussed. © 2015 Wiley Periodicals, Inc.
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| 5. |
- Mertens, Fredrik, et al.
(författare)
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The emerging complexity of gene fusions in cancer.
- 2015
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Ingår i: Nature Reviews. Cancer. - : Springer Science and Business Media LLC. - 1474-1768 .- 1474-175X. ; 15:6, s. 371-381
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Forskningsöversikt (refereegranskat)abstract
- Structural chromosome rearrangements may result in the exchange of coding or regulatory DNA sequences between genes. Many such gene fusions are strong driver mutations in neoplasia and have provided fundamental insights into the disease mechanisms that are involved in tumorigenesis. The close association between the type of gene fusion and the tumour phenotype makes gene fusions ideal for diagnostic purposes, enabling the subclassification of otherwise seemingly identical disease entities. In addition, many gene fusions add important information for risk stratification, and increasing numbers of chimeric proteins encoded by the gene fusions serve as specific targets for treatment, resulting in dramatically improved patient outcomes. In this Timeline article, we describe the spectrum of gene fusions in cancer and how the methods to identify them have evolved, and also discuss conceptual implications of current, sequencing-based approaches for detection.
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| 6. |
- Mitelman, Felix, et al.
(författare)
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The impact of translocations and gene fusions on cancer causation.
- 2007
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Ingår i: Nature Reviews. Cancer. - : Springer Science and Business Media LLC. - 1474-1768 .- 1474-175X. ; 7:4, s. 233-245
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Forskningsöversikt (refereegranskat)abstract
- Chromosome aberrations, in particular translocations and their corresponding gene fusions, have an important role in the initial steps of tumorigenesis; at present, 358 gene fusions involving 337 different genes have been identified. An increasing number of gene fusions are being recognized as important diagnostic and prognostic parameters in malignant haematological disorders and childhood sarcomas. The biological and clinical impact of gene fusions in the more common solid tumour types has been less appreciated. However, an analysis of available data shows that gene fusions occur in all malignancies, and that they account for 20% of human cancer morbidity. With the advent of new and powerful investigative tools that enable the detection of cytogenetically cryptic rearrangements, this proportion is likely to increase substantially.
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