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Schwab, Manfred; Praml, Christian; Amler, Lukas C.
doi: 10.1002/(SICI)1098-2264(199608)16:4<211::AID-GCC1>3.3.CO;2-Dpmid: N/A
Both cytogenetic and molecular genetic approaches have unveiled non‐random genomic alterations in Ip associated with a number of human malignancies. These have been interpreted to suggest the existence of cancer‐related genes in Ip. Earlier studies had employed chromosome analysis or used molecular probes mapped by in situ hybridization. Further, studies of the various tumor types often involved different molecular probes that had been mapped by different technical approaches, like linkage analysis, radioactive or fluorescence in situ hybridization, or by employing a panel of mouse × human radiation reduced somatic cell hybrids. The lack of maps fully integrating all loci has complicated the generation of a comparative and coherent picture of Ip damage in human malignancies even among different studies on the same tumor type. Only recently has the availability of genetically mapped, highly polymorphic loci at (CA)n repeats with sufficient linear density made it possible to scan genomic regions in different types of tumors readily by polymerase chain reaction (PCR) with a standard set of molecular probes. This paper aims at presenting an up‐to‐date picture of the association of Ip alterations with different human cancers and compiles the corresponding literature. From this it will emerge that the pattern of alterations in individual tumor types can be complex and that a stringent molecular and functional definition of the role that Ip alterations might have in tumorigenesis will require a more detailed analysis of the genomic regions involved. Genes Chromosom Cancer 16:211–229 (1996). © 1996 Wiley‐Liss, Inc.
Meijne, E.I. M.; Silver, A.R. J.; Bouffler, S. D.; Morris, D. J.; van Kampen, E. Winter; Spanjer, S.; Huiskamp, R.; Cox, R.
doi: 10.1002/(SICI)1098-2264(199608)16:4<230::AID-GCC2>3.3.CO;2-Bpmid: N/A
A previous study indicated that a highly inbred CBA/H mouse colony contained four genotypic variants for telomere‐like repeat (TLR) sequence arrays and that one variant subpopulation that constituted 20% of the colony contributed the vast majority (>90%) of radiation‐induced acute myeloid leukaemias (AMLs). Through screening of a satellite CBA/H colony and rescreening of the original colony, we show that, whereas germline telomere sequence polymorphism is frequent in CBA/H mice, there is no genetic link between a specific TLR locus variant and susceptibility to AML. Studies on telomere‐hybridising fragments between 200 bp and 150 kb revealed that the germline telomere mutation frequency was highest for restriction fragments>50 kb. The hypervariability of these high‐molecular‐weight fragments resulted in each CBA/H mouse from the highly inbred colony having a different genotype. Although it was not possible to ascribe a specific somatic telomere mutation to AML development, telomere rearrangements were common in induced AMLs. Some terminal telomere‐hybridising restriction fragments were shortened in AML samples in comparison with normal tissue, but, insofar as the reduction in size was relatively small, it seems unlikely that telomere erosion is a major contributor to the molecular pathology of murine radiation‐induced AML. Genes Chromosom Cancer 16:230–237 (1996). © 1996 Wiley‐Liss, Inc.
Clark, D. J.; Meijne, E.I. M.; Bouffler, S. D.; Huiskamp, R.; Skidmore, C. J.; Cox, R.; Silver, A.R. J.
doi: 10.1002/(SICI)1098-2264(199608)16:4<238::AID-GCC3>3.3.CO;2-Lpmid: N/A
Deletions and/or rearrangements involving one copy of chromosome 2 are consistent and early events in the development of murine acute myeloid leukaemia (AML) by radiation. More than 90% of AMLs induced in the CBA strain of mice express such cytogenetic alterations, with chromosome 2 breakpoints clustering in the C and F regions of the chromosome. In inbred mouse strains, the molecular resolution of these breakpoints is problematic. However, by using x‐ray‐induced AMLs in FI progeny of genetically divergent CBA/H × C57BI, it has been possible to show region‐specific loss of heterozygosity (LOH) in genetically linked sets of chromosome 2 microsatellite alleles from one of the two parental chromosomes. In the majority of cases, an acceptable concordance was shown for AML chromosome 2 deletion, as defined by microsatellites and as revealed by G‐band cytogenetics. A degree of breakpoint clustering was found, but the identification of a number of deletion types, based on the position of proximal and distal breakpoints as defined by microsatellite analysis, strongly supports a leukaemogenic mechanism involving gene deletion. No bias towards loss of CBA or C57BI alleles was observed, and the gender of AML‐presenting animals did not appear to influence the parental origin of the deletions. A molecular map of chromosome 2 breakpoints has now been established in FI AMLs as a first step towards the molecular cloning of breakpoint sequences. Genes Chromosom Cancer 16:238–246 (1996). © 1996 Wiley‐Liss, Inc.
Mautner, Josef; Bornkamm, Georg W.; Polack, Axel
doi: 10.1002/(SICI)1098-2264(199608)16:4<247::AID-GCC4>3.3.CO;2-Kpmid: N/A
The identification of cis‐acting regulatory elements has been greatly facilitated by the perception that nonnucleosomal regions of chromatin, including sites where transacting factors are bound, are hypersensitive to cleavage by nucleases. Hence, mapping of DNasel‐hypersensitive sites (HSs) has become particularly valuable for the detection of transcriptional control elements. The utility of this technique, however, may be constrained by the huge size of some eukaryotic gene domains or by the nonavailability of genomic probes. Apparently, both of these drawbacks hold true for the human protooncogene MYC. To overcome these limitations, we investigated the feasibility of mapping DNasel‐HSs in large restriction fragments. By using MYC‐amplified cell lines, we devised a simple protocol that allowed for the detection of DNasel‐HSs at a distance of several hundred kb. In an attempt to identify additional regulatory elements required for MYC expression, we used this method to establish the long‐range chromatic structure of four MYC amplicons. This method has potential benefits and applications. Genes Chromosom Cancer 16:247–253 (1996). © 1996 Wiley‐Liss, Inc.
Arden, Karen C.; Anderson, Michael J.; Finckenstein, Friedrich Graf; Czekay, Suzanne; Cavenee, Webster K.
doi: 10.1002/(SICI)1098-2264(199608)16:4<254::AID-GCC5>3.3.CO;2-Ppmid: N/A
Rhabdomyosarcoma, a small‐, round‐cell tumor of skeletal muscle, is the most common soft tissue sarcoma found in children. A specific and unique chromosomal translocation, t(2;13)(q35;q14), has been described cytogenetically in a subset of these tumors and is most often associated with the alveolar histologic subtype. The cloning and sequencing of complementary DNA from fusion transcripts expressed by both cell lines and tumors have shown that this chromosomal translocation results in the fusion of the PAX3 gene on chromosome 2 with a member of the forkhead gene family, FKHR, on chromosome 13. To detect this genetic abnormality we have developed a sensitive method which relies on a reverse transcriptase‐polymerase chain reaction with primers designed to be specific for the chromosome 2 and chromosome 13 sides of the translocation. The utility of this approach was tested by analyzing a series of rhabdomyosarcoma cell lines and tumor samples. The data demonstrate that the transcripts derived from the t(2; 13) were restricted to tumors having features of the alveolar subtype and that they could be detected with greater ease and sensitivity than with cytogenetic analysis. This approach will facilitate a large‐scale group effort to determine the frequency as well as the prognostic and diagnostic significance of this chromosomal rearrangement. Genes Chromosom Cancer 16:254–260 (1996). © 1996 Wiley‐Liss, Inc.
Dierlamm, Judith; Wlodarska, Iwona; Michaux, Lucienne; La Starza, Roberta; Zeller, Wolfgang; Mecucci, Cristina; Van den Berghe, Herman
doi: 10.1002/(SICI)1098-2264(199608)16:4<261::AID-GCC6>3.3.CO;2-Upmid: N/A
The feasibility of using the same slide repeatedly for fluorescence in situ hybridization (FISH) experiments was systematically evaluated by applying standard procedures and various combinations of direct‐ and indirect‐labeled probes to slides from patients with hematologic malignancies. Specific and distinct hybridization signals along with weak background signals and chromosome morphology of good to moderate quality could be obtained in up to three experiments performed consecutively on the same slide. Signals related to biotin‐ or digoxigenin‐labeled probes applied in previous hybridizations were still visible with variable intensity, but interpretation problems that may result from this signal noise can be avoided by using adequate probes, detection systems and fluorochromes, and sequence of experiments. Genes Chromosom Cancer 16:261–264 (1996). © 1996 Wiley‐Liss, Inc.
Simon, Matthias; Kokkino, Andrew J.; Warnick, Ronald E.; Tew, John M.; von Deimling, Andreas; Menon, Anil G.
doi: 10.1002/(SICI)1098-2264(199608)16:4<265::AID-GCC7>3.3.CO;2-Fpmid: N/A
Microsatellite length instability, probably resulting from defective DNA mismatch repair mechanisms, has been described in a variety of cancers. Such genetic instability may play a significant role in tumor formation and progression. To investigate the role of microsatellite alterations in meningioma tumorigenesis and progression, we examined 33 microsatellite markers on nine chromosomes for abnormalities in 18 benign, 15 atypical, and 11 malignant meningiomas. In each tumor, at least 15 markers were investigated. Microsatellite instability was not detected in any of the cases examined. However, loss of heterozygosity for markers from various chromosomes was seen frequently among atypical and malignant meningiomas. Although some of these chromosomal losses might represent random events, our data also indicate a role for specific loci on chromosome arms 14q, 1p, 10q, and possibly 9p in the development of malignancy in meningiomas. Our results argue against a significant role for a generalized microsatellite instability phenotype in meningiomas, but they suggest that genomic instability resulting in frequent allelic deletions may contribute to meningioma progression. Genes Chromosom Cancer 16:265–269 (1996). © 1996 Wiley‐Liss, Inc.
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