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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present karyotypes of 15 meningiomas with structural aberrations of chromosome 7, which were taken from a consecutive series of 400 cytogenetically characterized meningiomas. Twelve of these tumors (80%) displayed partial or complete monosomy 7p with a consensus deleted region of 7p12 approximately pter, in 6 of 15 cases arising from an unbalanced whole-arm t(1;7)(q11;p11), and in 4 of 15 cases from a whole-arm translocation involving other chromosomes. Other types of partial aneusomy 7 (3/15 cases) or balanced aberrations of chromosome 7 (2/15 cases) were relatively rare. In most cases (11/15), the centromeric region of chromosome 7 was involved in the rearrangements. We conclude that in meningiomas, the near-centromeric region of chromosome 7 is particularly prone to structural rearrangements most frequently resulting in monosomy 7p. The investigation of the histopathologic features of this rare cytogenetic subgroup of meningiomas showed no clear genotype/phenotype correlation. As 7 of 11 of the meningiomas with monosomy 7p belonged to World Health Organization grades II or III, which usually comprise less than 20% of all meningiomas, partial loss of 7p appears to be involved in tumor progression in meningiomas. Because monosomy 7p is typically associated with the strongly progression-associated monosomy 1p, however, monosomy 7p represents a cofactor more than a stand-alone feature of meningioma progression.
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PMID:Monosomy 7p in meningiomas: a rare constituent of tumor progression. 1281 Feb 58

All invasive testicular germ cell tumors of adolescents and adults (TGCTs), that is, seminomas and nonseminomas, show gain of 12p sequences, mostly as isochromosomes. Although several candidate genes have been suggested, the relevant gene(s) have not been identified yet. About 10% of testicular seminomas, however, show a more restricted amplification of the 12p11.2-p12.1 region, in which the various amplicons show an apparent overlap, allowing for the shortest region of amplification overlap approach, aiming at the identification of pathogenetically relevant sequences residing in this region. Here we report on a high-resolution 12p-amplicon architecture analysis using microarray-based comparative genomic hybridization, the results of which were subsequently confirmed by fluorescent in situ hybridization studies. The 12p-specific microarray contained 63 positionally selected BAC clones, which are more or less evenly distributed over the short arm of chromosome 12 (average spacing: less than 500 Kb), including 20 clones within the region of amplification. Out of a series of 17 seminomas, seven seminomas showed amplification of the whole amplicon region, of which three showed a dip in T/R value in the center of the amplified area. A more complex amplification pattern was found in the other 10 seminomas: three showed predominant amplification at the centromeric border; one mainly at the telomeric border; six showed a balanced amplification of both the centromeric and telomeric regions. The only nonseminoma investigated showed a structure in which the centromeric border was only amplified. These data support a mechanistic model in which at least two 12p genes, situated at the border regions of the amplicon, are positional candidates capable of actively supporting tumor progression in TGCTs.
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PMID:12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH. 1457 33

Several chromosome defects parallel morphologic evolution in colorectal tumor progression. Allelic losses in the short arm of chromosome 17, the majority encompassing the 17p13.3 band, have been found in advanced cancer in the absence of TP53 mutations, suggesting that loss of genes in this chromosome region is relevant for tumorigenesis. The aim of this study was to investigate 17p13.3 deletions throughout the colorectal tumor progression using two-color fluorescence in situ hybridization. Histologic sections from 20 colorectal adenomas containing early invasive carcinoma were analyzed by interphase fluorescence in situ hybridization using a centromeric probe for chromosome 17 simultaneously with a subtelomeric probe mapping to the 17p13.3 band. Separate evaluation was made for sectors corresponding to adenoma tissue with low-grade dysplasia, high-grade dysplasia, and early cancer. The same technique was also used in 20 cases of advanced adenocarcinoma of the large bowel. Loss of one centromeric signal was observed in 20, 40, 50, and 10% of low-grade dysplasia, high-grade dysplasia, early cancer, and advanced cancer, respectively (P<0.02 early vs. advanced cancer). Subtelomeric 17p deletions were seen in 60% of advanced cancer and in 15% of early cancer (P<0.01). These findings indicate that loss of genes from the 17p13.3 chromosome region may play an important role in sustaining the transition from early to advanced cancer in colorectal tumor progression.
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PMID:Deletions of 17p are associated with transition from early to advanced colorectal cancer. 1458 Jul 70

Clinical relevance and stage correlation of telomerase activity in well-differentiated papillary thyroid carcinoma (WD PTC) has not been well determined, as its reported activity could be due to the analysis of tumors with lymphocytic infiltrates or aggressive variants of papillary carcinomas. We conducted a prospective study of telomerase activity in WD PTC without inflammatory infiltrates and correlated it with clinical stage. Fifty WD PTCs were analyzed for telomerase activity by PCR-based TRAP (telomeric repeat amplification protocol) assay. Results were correlated with stage and other clinicopathologic variables. Twenty-one (42%) WD PTCs demonstrated telomerase activity. The enzyme was detected more frequently in stage III/IVa WD PTCs (p = 0.02) and in tumors with extra thyroidal extension (p = 0.04). The risk of presenting advanced disease (stage III/IVa) and extrathyroidal growth was significantly increased in telomerase-positive tumors (p = 0.01; odds ratio [OR] 4.4 [95%CI 1.3-14.7]) and (p = 0.04; OR 3.6 [95%CI 1.1-11.7]), respectively. Also, a correlation was found between telomerase activity and age. There was no correlation of telomerase activity with gender, histologic variant, tumor size, or cervical lymph node metastasis. Telomerase activity was observed in 42% of WD PTC and was detected more frequently in AJCC TNM stage III/IVa cases. This finding suggests that telomerase deregulation could be involved in tumor progression.
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PMID:Telomerase activity in well-differentiated papillary thyroid carcinoma correlates with advanced clinical stage of the disease. 1458 66

Cutaneous melanoma is a highly aggressive tumor that is relatively resistant to chemotherapy and radiotherapy. This resistance may be in part due to inhibition of apoptosis. Apoptotic protease activating factor-1(APAF-1), a candidate tumor suppressor gene, mediates p53-induced apoptosis, and its loss promotes oncogenic transformation. To determine whether loss of the APAF-1 locus influences tumor progression, we assessed loss of heterozygosity microsatellites on the APAF-1 locus (12q22-23) in 62 primary and 112 metastatic melanomas. We discovered that frequency of allelic imbalance was significantly higher in metastatic tumors (n = 36 of 98; 37%) than in primary melanomas (n = 10 of 54; 19%; P = 0.02). In metastatic melanomas, APAF-1 loss significantly correlated with a worse prognosis (P < 0.05) in the patients, and its loss during melanoma tumor progression suggests that APAF-1 is a tumor suppressor gene. Furthermore, loss of heterozygosity was frequent in the 12q22-23 chromosome region centromeric to the APAF-1 locus suggesting that other tumor-related genes may be present in the 12q22-23 region. In summary, the study demonstrates that allelic imbalance in the 12q22-23 region is a genomic surrogate of poor disease outcome for cutaneous melanoma patients.
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PMID:Allelic imbalance of 12q22-23 associated with APAF-1 locus correlates with poor disease outcome in cutaneous melanoma. 1502 69

Hypoxia-inducible factor 1 (HIF-1) is a key regulator of O(2) homeostasis, which regulates the expression of several genes linked to angiogenesis and energy metabolism. Tumor hypoxia has been shown to be associated with poor prognosis in a variety of tumors, and HIF-1 induced by hypoxia plays pivotal roles in tumor progression. The presence of putative HIF-1-binding sites on the promoter of human telomerase reverse transcriptase gene (hTERT) prompted us to examine the involvement of HIF-1 in the regulation of hTERT and telomerase in tumor hypoxia. The telomeric repeat amplification protocol (TRAP) assay revealed that hypoxia activated telomerase in cervical cancer ME180 cells, with peak induction at 24-48 h of hypoxia. Notably, hTERT mRNA expression was upregulated at 6-12 h of hypoxia, concordant with the elevation of HIF-1 protein levels at 6 h. hTERT protein levels were subsequently upregulated at 24 h and later. Luciferase assays using reporter plasmids containing hTERT core promoter revealed that hTERT transcription was significantly activated in hypoxia and by HIF-1 overexpression, and that the two putative binding sites within the core promoter are responsible for this activation. Chromatin immunoprecipitation assay identified the specific binding of HIF-1 to these sites (competing with c-Myc), which was enhanced in hypoxia. The present findings suggest that hypoxia activates telomerase via transcriptional activation of hTERT, and that HIF-1 plays a critical role as a transcription factor. They also suggest the existence of novel mechanisms of telomerase activation in cancers, and have implications for the molecular basis of hypoxia-induced tumor progression and HIF-1-based cancer gene therapy.
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PMID:HIF-1-mediated activation of telomerase in cervical cancer cells. 1504 86

Despite the wide range of probes commercially available for interphase fluorescence in situ hybridisation (FISH), the supply of locus-specific probes is limited to genes or chromosomal regions commonly altered in genetic diseases or during carcinogenesis. Generation of these probes is therefore desirable to accommodate individual research requirements. Hence, we detail the methodology required to design and produce custom locus-specific interphase FISH probes for any human genomic region of interest and their application was illustrated in cytogenetic investigations of Barrett's tumourigenesis. Previously utilising FISH, we observed that Barrett's tissues demonstrated chromosome 4 hyperploidy [Gut 52 (2003) 623], but as centromeric probes were used in this analysis, it was not known if the whole chromosome was amplified. We consequently generated single-copy sequence probes for the 4p16.3 and 4q35.1 subtelomeric loci. Multicolour FISH was subsequently performed on interphase preparations originating from patients with Barrett's esophagus at varying histological grades, thus demonstrating the whole region of chromosome 4 was amplified within the tissues. Additionally, probes for the DNA methyltransferase genes were produced to determine if gene dosage alterations were responsible for increasing methylation activity during Barrett's neoplastic progression. No significant alterations at the DNMT1 and DNMT3a loci were detected. An increased copy number of these genes is therefore not the basis for the hypermethylation commonly observed in this premalignant lesion.
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PMID:Generation of locus-specific probes for interphase fluorescence in situ hybridisation--application in Barrett's esophagus. 1521 47

This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. Fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.
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PMID:An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma. 1525 20

Activation of telomerase plays a critical role in unlimited proliferation and immortalization of cells. Telomerase activity has been shown to correlate with tumor progression, indicating that tumors expressing this enzyme possess aggressive clinical behavior and that telomerase activity may be a useful biomarker for early detection of cancer. However, measurements of telomerase activity by current methods such as telomeric repeat amplification protocol (TRAP)/polymerase chain reaction (PCR) or antibody-based radioimmunoassay (RIA) are low-throughput and not robust enough to easily accommodate the required statistical analysis to determine whether telomerase activity is a practical biomarker. As part of the National Cancer Institute Early Detection Research Network of analytical validation, we have developed a robot assisted TRAP assay (RApidTRAP) of telomerase, a potential biomarker for cancer early detection. Measurements of human telomerase reverse transcriptase catalytic subunit (hTERT) mRNA were performed in concert with measurement of telomerase activity. For this purpose we determined hTERT mRNA concentration and telomerase activity in human normal (RPE-28) and cancer (A549) cell lines as well as in human serum (SRM 1951A). Telomerase activity measurements were made using the TRAP/PCR capillary electrophoresis (CE) method on (50 to 1000) cells/reaction isolated from cell extracts. Measurement of hTERT mRNA was made using specific primers and probes on a LightCycler in the range of (10 to 7000) cells/reaction. Comparison of high-throughput telomerase activity measurements using the robot and those performed manually were consistent in sensitivity and reproducibility. Using this combination of telomerase activity and hTERT mRNA measurements, the automated system improved efficiency over traditional TRAP/PCR methods.
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PMID:Analytical validation of telomerase activity for cancer early detection: TRAP/PCR-CE and hTERT mRNA quantification assay for high-throughput screening of tumor cells. 1526 91

It has been known for more than a century that neoplastic cells often exhibit disturbances of the mitotic process, but the causes have only recently been thoroughly explored. In many cancers, a combination of cell cycle checkpoint deficiency and abnormal shortening of telomeres predisposes to unbalanced chromosome segregation at cell division and the development of complex genomic rearrangements. Shortening of telomeric repeats beyond normal limits leads to fusion of chromosome ends and the formation of chromatin bridges at anaphase. In turn, these bridges may trigger at least three types of chromosomes mutation: (1) structural rearrangements of chromosomes through extensive chromatin fragmentation beyond the centromeric sequences, typically leading to the formation of isochromosomes and whole-arm translocations, (2) loss of whole chromosomes through mechanical detachment from the mitotic spindle machinery, and (3) failure of cytokinesis, leading to polyploidisation and supernumerary centrosomes, which may in turn orchestrate multipolar spindle configurations at a subsequent mitosis. Anaphase bridging rarely hinders further survival of tumor daughter cells. In contrast, multipolar mitoses may lead to extensive reshuffling of chromosome copies that compromise further clonal expansion. The telomere-dependent instability can be partly counteracted by expression of telomerase during tumor progression, but genomic stabilisation is rarely, if ever, complete.
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PMID:Mitotic instability in cancer: is there method in the madness? 1608 99


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