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 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Structural chromosomal aberrations are common in epithelial tumors. Here, we compared the location of centromeric breaks associated with whole arm translocations in seven adenocarcinoma cell lines and nine squamous cell carcinoma cell lines using SKY, microarray-based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH). Whole arm translocations were more frequent in squamous cell carcinomas (112 in nine cell lines and nine in one short-term culture) than in adenocarcinomas (13 in seven cases) and most often resulted in copy number alterations. Array CGH analysis demonstrated that in all squamous cell carcinomas and in most adenocarcinomas, the breakpoints of unbalanced whole arm translocations occurred between the two clones on the array flanking the centromeres. However, FISH with centromeric probes revealed that in squamous cell carcinomas, the marker chromosomes with whole arm translocations contained centromeres comprised of material from both participating chromosomes, while in adenocarcinomas centromeric material from only one of the chromosomes was present. These observations suggest that different mechanisms of centromeric instability underlie the formation of chromosomal aberrations in adenocarcinomas and squamous cell carcinomas.
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PMID:Centromeric chromosomal translocations show tissue-specific differences between squamous cell carcinomas and adenocarcinomas. 1567 45

Gene amplification, an important mechanism of oncogene activation in breast cancer, can have both prognostic and therapeutic implications. In this work, an attempt is made to identify amplified genes that can be used to improve prognostication in breast cancer. A series of 52 node-negative tumours was screened for genomic gains at 57 loci by array-CGH. A subset of these genes was identified that could divide the series into two divergent outcome groups of either long-term survivors or early disease-related deaths (p = 0.01) using a combination of k-means clustering and statistical analysis. The prognostic significance of amplification of four of the genes (EMS1, TOP2A, CCNE1, and ERBB2) was then evaluated, using fluorescent in situ hybridization on a tissue microarray, in a second larger 'validation' series of 232 tumours with a median follow-up of 4.8 years. Adverse disease-related outcome was associated with amplification of TOP2A (p = 0.004); ERBB2 (p = 0.002); and with the combined amplification of TOP2A, ERBB2, and EMS1 (p = 0.01). EMS1 amplification was more common (26% of cases) than previously reported but, in isolation, had no prognostic significance. Amplification of CCNE1, seen in only 6% of cases, had no prognostic role. These results indicate that the complementary use of array-CGH and tissue microarrays has the potential to help in the identification and validation of molecular markers that can be used to classify breast cancers into different prognostic groups.
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PMID:Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissue microarrays. 1568 39

Survival for patients with squamous cell carcinoma of the head and neck (SCCHN) is still poor, despite great technical improvements in radiotherapy and surgery. A possible explanation for this is the lack of individualization in treatment based on biological properties of the tumors, resulting in over- as well as under treatment. Management of SCCHN has mainly been based on TNM classification over the last decades. However, a large amount of studies have shown that biomarkers may add prognostic information, independently of the TNM system, indicating that biological aggressiveness is not entirely reflected by the T- and N-status of the tumor. A conclusion to draw from this is that the present standardized treatment based on macroscopic features of the tumor in many cases will result in suboptimal treatment since important underlaying genetic properties of the tumors are not taken into consideration. A variety of laboratory techniques have been used in studies that investigate the individual biological features, spanning from methods that screen the genome for chromosomal and genetic abnormalities, e.g. cytogenetics, CGH, SKY, cDNA micro array to detailed studies of specific aberrations, e.g. southern, northern and western blotting, PCR based analysis and immunohistochemistry. Dysregulation of genes involved in e.g. cell cycle control, proliferation, drug resistance, and metastasis have been linked to outcome of treatment and survival. The purpose of this review of the literature was to summarize what has been studied so far by cDNA micro array techniques with regards to genetic screening in general and biomarkers that relate to response to therapy and prediction of clinical outcome in particular. We conclude that the majority of investigations that focus on gene profiling have a descriptive character, e.g. comparisons of tumor and normal cells, metastatic and non-metastatic properties, and differences between sub-sites and grades of differentiation. There are just a handful studies that so far have investigated how gene profiling can be used to predict clinical course.
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PMID:Gene profiling in squamous cell carcinoma of the head and neck. 1578 74

We have developed a method to suppress the PCR amplification of repetitive sequences in whole chromosome painting probes by adding Cot-1 DNA to the amplification mixture. The repetitive sequences in the Cot-1 DNA bind to their homologous sequences in the probe library, prevent the binding of primers, and interfere with extension of the probe sequences, greatly decreasing PCR efficiency selectively across these blocked regions. A second labelling reaction is then done and this product is resuspended in FISH hybridization mixture without further addition of blocking DNA. The hybridization produces little if any non-specific binding on any other chromosomes. We have been able to successfully use this procedure with both human and rat chromosome probes. This technique should be applicable in producing probes for CGH, M-FISH and SKY, as well as reducing the presence of repetitive DNA in genomic libraries.
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PMID:Polymerase chain reaction-based suppression of repetitive sequences in whole chromosome painting probes for FISH. 1579 9

Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the gastrointestinal tract (GIT). They represent a wide clinico-pathological spectrum of tumors. No single histological or clinical parameter can predict the prognosis while the response to therapy is related to the type of KIT or PDGFRA mutation. Cytogenetic and CGH studies have identified frequent gross chromosomal aberrations but the target genes of these changes are unknown. To determine whether known oncogenes take part in genomic rearrangements and to investigate the potential clinical significance of their amplifications, nine known oncogenes (CMYC, MDM2, GLI1, CDK4, HER2, EGFR1, CCND1, FGF3, EMS) were analyzed by fluorescent in situ hybridization (FISH) on a tissue microarray (TMA) containing 94 primary GIST. Clinical follow-up information was available for 57 of these patients. Amplification was found for CMYC in three of 90 (3.3%), for MDM2 in five of 94 (5.3%), for EGFR1 in five of 94 (5.3%), and for CCND1 in seven of 79 (8.9%) evaluable cases. No amplifications were seen for HER2, GLI1, CDK4, FGF3, and EMS. Amplifications of MDM2 and CCND1 were associated with clinical and histological malignancy. In conclusion, our data show that gene amplification does occur in a subset of GIST. Identification of MDM2/CCND1 amplification may represent another molecular feature that could help in the evaluation of the behavior of GISTs.
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PMID:Patterns of gene amplification in gastrointestinal stromal tumors (GIST). 1586 17

To catalog data on chromosomal aberrations in cancer derived from emerging molecular cytogenetic techniques and to integrate these data with genome maps, we have established two resources, the NCI and NCBI SKY/M-FISH & CGH Database and the Cancer Chromosomes database. The goal of the former is to allow investigators to submit and analyze clinical and research cytogenetic data. It contains a karyotype parser tool, which automatically converts the ISCN short-form karyotype into an internal representation displayed in detailed form and as a colored ideogram with band overlay, and also has a tool to compare CGH profiles from multiple cases. The Cancer Chromosomes database integrates the SKY/M-FISH & CGH Database with the Mitelman Database of Chromosome Aberrations in Cancer and the Recurrent Chromosome Aberrations in Cancer database. These three datasets can now be searched seamlessly by use of the Entrez search and retrieval system for chromosome aberrations, clinical data, and reference citations. Common diagnoses, anatomic sites, chromosome breakpoints, junctions, numerical and structural abnormalities, and bands gained and lost among selected cases can be compared by use of the "similarity" report. Because the model used for CGH data is a subset of the karyotype data, it is now possible to examine the similarities between CGH results and karyotypes directly. All chromosomal bands are directly linked to the Entrez Map Viewer database, providing integration of cytogenetic data with the sequence assembly. These resources, developed as a part of the Cancer Chromosome Aberration Project (CCAP) initiative, aid the search for new cancer-associated genes and foster insights into the causes and consequences of genetic alterations in cancer.
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PMID:The interactive online SKY/M-FISH & CGH database and the Entrez cancer chromosomes search database: linkage of chromosomal aberrations with the genome sequence. 1593 46

Gene mutations play a critical role in cancer development and progression, and their identification offers possibilities for accurate diagnostics and therapeutic targeting. Finding genes undergoing mutations is challenging and slow, even in the post-genomic era. A new approach was recently developed by Noensie and Dietz to prioritize and focus the search, making use of nonsense-mediated mRNA decay (NMD) inhibition and microarray analysis (NMD microarrays) in the identification of transcripts containing nonsense mutations. We combined NMD microarrays with array-based CGH (comparative genomic hybridization) in order to identify inactivation of tumor suppressor genes in cancer. Such a "mutatomics" screening of prostate cancer cell lines led to the identification of inactivating mutations in the EPHB2 gene. Up to 8% of metastatic uncultured prostate cancers also showed mutations of this gene whose loss of function may confer loss of tissue architecture. NMD microarray analysis could turn out to be a powerful research method to identify novel mutated genes in cancer cell lines, providing targets that could then be further investigated for their clinical relevance and therapeutic potential.
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PMID:NMD microarray analysis for rapid genome-wide screen of mutated genes in cancer. 1603 37

Conventional cytogenetic analysis of chromosome abnormalities in hematologic malignancies is hampered by the low mitotic index and poor quality of metaphases. A range of techniques based on fluorescence in situ hybridization (FISH) has greatly enhanced the identification of non-random translocations and deletions, pinpointing regions which contain genes involved in leukemogenesis. One of the main advantages of FISH is its ability to use non-dividing interphase cells as DNA targets, enabling the screening of large numbers of cells and providing access to a variety of cells with different hematopoetic activity. Furthermore, multicolor FISH (SKY, M-FISH and CGH microarrays) combines the screening potential of cytogenetics with the accuracy of molecular genetics, allowing the visualization of the entire human genome in 24 different colors.
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PMID:Impact of cytogenetic and molecular cytogenetic studies on hematologic malignancies. 1608 May 55

We report the complex cytogenetic analysis of a novel melanoma cell line (M35/01) established from a vertical growth phase of a superficial spreading melanoma. Similarly to its parental tumor, this cell line metastasizes to the liver. Using combined molecular cytogenetic techniques, we could identify a reservoir of chromosomal alterations in M35/01. In addition, we had sufficient amount of DNA from both the original primary tumor and the cell line which allowed for the comparison of their genetic patterns by chromosomal CGH. Several common alterations were found indicating the same clonal origin. These alterations included gains of 6p, 7q, 15q and deletions of 9, 10, 16q and 17p. Chromosomal losses present only in the cell line were detected on chromosome 4, 16p, 18 and gains on 20p12-qter. Array CGH analysis of the M35/01 cell line provided similar results with a much higher resolution, representing relatively high level gains on 7q31.2-q31.31, 15q25, 20q, and losses on 4q28, 9p21-p24, 9q21-q22, 10q25, 16q13-q23, 17p12-13 and 18q12-23. Using SKY-FISH, several structural alterations could be detected which were not recognized by conventional cytogenetics. Except for chromosome 18, none of the centromeres showed normal distribution by FISH. Our analysis shows that a high number of chromosomal alterations, which are known to be nonrandomly associated with melanoma progression, can be found by the combined use of different molecular genetic techniques. This new melanoma cell line would be an excellent model for investigating the mechanism of organ specific-metastatic events of malignant melanoma.
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PMID:Molecular cytogenetic characterization of a novel cell line established from a superficial spreading melanoma. 1636 60


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