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1.
M Talagas P Marcorelles A Uguen S Redon I Quintin-Roué S Costa C Férec F Morel PD Hieu M De Braekeleer 《Journal of neuro-oncology》2012,109(2):405-413
Oligodendroglial tumors (ODTs) are primary tumors of the central nervous system that show recurrent codeletion of whole chromosome arms 1p and 19q. Non-1p/19q-deleted high-grade ODTs can present other genetic aberrations, CDKN2A deletion (9p21.3), EGFR amplification (7p11.2) and/or chromosome 10 loss, which are associated with a poor prognosis. The identification of these abnormalities allowed drafting a histo-molecular classification. The aim of this study was to precisely identify, using array CGH, the genomic hallmarks of these tumors, particularly those that are not deleted on 1p/19q. We studied 14 formalin-fixed paraffin-embedded high-grade ODTs using pangenomic oligonucleotide array CGH with an average resolution of 22.3 kb. The 1p/19q codeletion was found in five anaplastic oligodendrogliomas. The three genomic aberrations carrying a poor prognosis were found, most often associated, in five out of nine tumors not deleted on 1p/19q. In addition, four recurrent copy number alterations, involving genes that participate to cell growth and cycle, were found to be strongly associated in five tumors not deleted on 1p/19q: gain or amplification at 1q32.1 (MDM4, PIK3C2B genes), 12q14.1 (CDK4 gene), 12q14.3-q15 (MDM2 gene) and homozygous deletion at 22q13.1 (APOBEC3B gene). MDM2, MDM4, CDK4 and PIK3C2B are known for potentially being amplified or overexpressed in high-grade gliomas. However, the involvement of APOBEC3B, coding for mRNA edition enzyme, is described here for the first time. Our results show a strong association between these four alterations. Therefore, this can open a perspective for a novel subgroup in high-grade ODTs not deleted on 1p/19q. 相似文献
2.
Persson F Winnes M Andrén Y Wedell B Dahlenfors R Asp J Mark J Enlund F Stenman G 《Oncogene》2008,27(21):3072-3080
We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1-PLAG1 gene fusions in which the 5'-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis. 相似文献
3.
Stine H Kresse Magne Skårn Hege O Ohnstad Heidi M Namløs Bodil Bjerkehagen Ola Myklebost Leonardo A Meza-Zepeda 《Molecular cancer》2008,7(1):48
Background
Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, and thereby novel gene targets of potential importance for MPNST development and/or progression, we have analyzed DNA copy number changes in seven high-grade MPNSTs using microarray-based comparative genomic hybridization (array CGH). 相似文献4.
The p53 network in lung carcinogenesis 总被引:8,自引:0,他引:8
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6.
Wang Huixin; Patel Vyomesh; Miyazaki Hiroshi; Gutkind J.Silvio; Yeudall W.Andrew 《Carcinogenesis》2009,30(1):165-174
We have investigated the role of the signaling intermediate,EPS8, in tumor progression using a model system and in vivo.HN4 primary tumor cells express low levels of EPS8, similarto normal keratinocytes, and show minimal invasion in vitroin response to epidermal growth factor, whereas HN12 cells expresshigh levels of EPS8 and are highly motile in vitro and tumorigenicin vivo. Additional independent tumor cell lines also showedelevated EPS8 expression compared with normal keratinocytes.Using retroviral transduction, we generated HN4 cell lines expressingEPS8 (HN4/EPS8) at levels equivalent to those present in HN12cells. HN4/EPS8 cells showed increased proliferation and migrationcompared with controls, together with elevated expression andactivity of matrix metalloprotease (MMP)-9, which was dependenton protein kinase B (AKT) activity. Introduction of plasmidsthat direct synthesis of EPS8 short hairpin RNA (shRNA) intoHN12 cells resulted in decreased EPS8 expression in these cells,which correlated with a decrease in their capacity to migrateand invade in vitro. In addition, shRNA-mediated knockdown ofEPS8 reduced expression and activity of MMP-9 produced by thesecells and reduced MMP-9 promoter activity. EPS8 knockdown cellsshowed decreased tumorigenicity in vivo compared with controlsand lower MMP-9 expression. Conversely, overexpression of EPS8in HN4 cells was sufficient to induce growth of these non-tumorigeniccells in orthotopic transplantation assays. Furthermore, EPS8expression in clinical samples of squamous cell carcinoma showedvariable expression levels and broadly paralleled expressionof MMP-9. The data support a role for EPS8 in squamous carcinogenesis. Abbreviations: AKT, protein kinase B; BSA, bovine serum albumin; cDNA, complementary DNA; DMEM, Dulbeccos modified Eagles medium; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; HNSCC, head and neck squamous cell carcinoma; MMP, matrix metalloprotease; PCR, polymerase chain reaction; PI3K, phosphoinositide 3-OH kinase; SCC, squamous cell carcinoma; shRNA, short hairpin RNA; qRT, quantitative real-time Received April 10, 2008; revised October 10, 2008; accepted November 1, 2008. 相似文献
7.
《Expert review of anticancer therapy》2013,13(11):1559-1568
Melanoma is one of the few tumors that have increased in incidence over the last few decades. Strategies devoted solely to protecting against ultraviolet radiation have, at best, had a modest impact on the development of melanoma. Chemoprevention is an under-explored approach that could significantly decrease the morbidity and mortality from this deadly cancer. However, the scientific and logistical challenges of performing clinical studies in chemoprevention require innovative approaches to prove the effectiveness of putative preventive agents. There are several pharmacological and nutriceutical agents that are mechanistically linked to events in melanoma carcinogenesis that are candidates for advanced human studies. We will review the data for several promising agents, including statins, curcumin, resveratrol, silymarin and green tea, and discuss some importance issues and concepts that should be considered in any melanoma chemoprevention strategy. 相似文献
8.
Melanoma is one of the few tumors that have increased in incidence over the last few decades. Strategies devoted solely to protecting against ultraviolet radiation have, at best, had a modest impact on the development of melanoma. Chemoprevention is an under-explored approach that could significantly decrease the morbidity and mortality from this deadly cancer. However, the scientific and logistical challenges of performing clinical studies in chemoprevention require innovative approaches to prove the effectiveness of putative preventive agents. There are several pharmacological and nutriceutical agents that are mechanistically linked to events in melanoma carcinogenesis that are candidates for advanced human studies. We will review the data for several promising agents, including statins, curcumin, resveratrol, silymarin and green tea, and discuss some importance issues and concepts that should be considered in any melanoma chemoprevention strategy. 相似文献
9.
12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH 总被引:3,自引:0,他引:3
Zafarana G Grygalewicz B Gillis AJ Vissers LE van de Vliet W van Gurp RJ Stoop H Debiec-Rychter M Oosterhuis JW van Kessel AG Schoenmakers EF Looijenga LH Veltman JA 《Oncogene》2003,22(48):7695-7701
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. 相似文献
10.
In this study, we present a case of parotid gland de novo carcinosarcoma. Salivary gland carcinosarcoma (or true malignant mixed tumor) is a rare biphasic neoplasm, composed of both malignant epithelial and malignant mesenchymal components. It is yet unclear whether these two phenotypes occur by collision of two independent tumors or if they are of clonal origin. To analyze the clonality of the different morphologic tumor components, oligonucleotide microarray-based comparative genomic hybridization (oaCGH) was performed on the carcinoma and the sarcoma entity separately. This technique enables a high-resolution, genome-wide overview of the chromosomal alterations in the distinct tumor elements. Analysis of both fractions showed a high number of DNA copy number changes. Losses were more prevalent than gains (82 and 49, respectively). The carcinomatous element displayed more chromosomal aberrations than the sarcomatous component. Specific amplifications of MUC20 (in mesenchymal element) and BMI-1 (in both elements) loci were observed. Overall homology between the two genomic profiles was 75%. DNA copy number profiles of the epithelial and mesenchymal components in this salivary gland carcinosarcoma displayed extensive overlap, indicating a monoclonal origin. Since losses are shared to a larger extent than gains, they seem to be more essential for initial oncogenic events. Furthermore, specific amplifications of a mucin and a Polycomb group gene imply these proteins in the tumorigenesis of carcinosarcomas. 相似文献
11.
Yoshitsugu Horio Aaron Chen Pamela Rice Jack A. Roth Alvin M. Malkinson David S. Schrump 《Molecular carcinogenesis》1996,17(4):217-223
In the A/J strain of mice, urethane (ethyl carbamate) induces lung hyperplasia, adenoma, and adenocarcinoma in a time-dependent manner. These distinct morphological stages may correlate with sequential molecular genetic changes in this mouse model. To test this hypothesis, we investigated the presence of mutations involving Ki-ras and p53 in urethane-induced lung lesions in A/J mice at early and late stages of tumorigenesis. We precisely microdissected 40 lung lesions from paraffin-embedded sections. Ki-ras mutations around codon 61 and p53 mutations in exons 5–8 were identified by polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing techniques. In 29 early-stage lung lesions classified as hyperplasias (seven) or adenomas (22), we observed 19 Ki-ras mutations (66%), including three silent mutations and one double mutation at different codons, and one silent p53 mutation (3.5%). In 11 late-stage adenomas, we identified nine activating Ki-ras mutations (82%) and four missense p53 mutations (36%). These results indicate that Ki-ras mutations arise early, whereas p53 mutations occur relatively late during the benign stages of urethane-induced lung carcinogenesis in A/J mice. © 1996 Wiley-Liss, Inc. 相似文献
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13.
Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes 总被引:8,自引:0,他引:8
Naturally occurring compounds belonging to two chemical groups were studied for their capacities to inhibit N-nitrosodiethylamine (NDEA)-induced carcinogenesis in female A/J mice. One group consists of organosulfur compounds found in Allium species, including garlic, onions, leeks, and shallots, and the other, two monoterpenes, i.e., D-limonene and D-carvone. In an initial experiment, in which organosulfur compounds were investigated, diallyl disulfide, allyl mercaptan, and allyl methyl disulfide were found to produce a marked inhibition of NDEA-induced neoplasia of the forestomach when the test compounds were administered p.o. 96 and 48 h prior to NDEA. The most potent was diallyl disulfide which reduced forestomach tumor formation by more than 90%. Pulmonary adenoma formation also was inhibited but to a considerably lesser extent, i.e., about 30%. In three additional experiments, test compounds were given p.o. either 15 min or 1 h prior to NDEA. Under these conditions diallyl disulfide and allyl mercaptan again inhibited forestomach tumor formation substantially, i.e., greater than 75%, and pulmonary adenoma formation marginally, i.e., less than 20%. In these experiments D-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35%. The results of these studies provide evidence of an increasing diversity of naturally occurring compounds having the capacity to inhibit nitrosamine carcinogenesis. 相似文献
14.
Chromosome 8q amplification is a common event observed in cancer. In this study, we used high-resolution array comparative genomic hybridization to resolve two neighboring regions on 8q that are both amplified in oral cancer. One region (at 8q24) contains the MYC oncogene, which is frequently overexpressed in many cancers, while the other region (at 8q22) represents a novel amplicon. The alignment of array comparative genomic hybridization profiles of 20 microdissected oral squamous cell carcinomas (OSCCs) revealed a approximately 5 Mbp region of frequent copy number alteration. This region harbors 16 known genes. Gene expression analysis comparing 15 microdissected OSCC with 16 normal epithelium samples revealed overexpression specific to LRP12 but not the neighboring genes, dihydropyrimidinase and FOG2, suggesting that LRP12 may function as an oncogene in oral tumors. 相似文献
15.
A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH 总被引:3,自引:0,他引:3
Roylance R Gorman P Papior T Wan YL Ives M Watson JE Collins C Wortham N Langford C Fiegler H Carter N Gillett C Sasieni P Pinder S Hanby A Tomlinson I 《Oncogene》2006,25(49):6544-6553
We analysed chromosome 16q in 106 breast cancers using tiling-path array-comparative genomic hybridization (aCGH). About 80% of ductal cancers (IDCs) and all lobular cancers (ILCs) lost at least part of 16q. Grade I (GI) IDCs and ILCs often lost the whole chromosome arm. Grade II (GII) and grade III (GIII) IDCs showed less frequent whole-arm loss, but often had complex changes, typically small regions of gain together with larger regions of loss. The boundaries of gains/losses tended to cluster, common sites being 54.5-55.5 Mb and 57.4-58.8 Mb. Overall, the peak frequency of loss (83% cancers) occurred at 61.9-62.9 Mb. We also found several 'minimal' regions of loss/gain. However, no mutations in candidate genes (TRADD, CDH5, CDH8 and CDH11) were detected. Cluster analysis based on copy number changes identified a large group of cancers that had lost most of 16q, and two smaller groups (one with few changes, one with a tendency to show copy number gain). Although all morphological types occurred in each cluster group, IDCs (especially GII/GIII) were relatively overrepresented in the smaller groups. Cluster groups were not independently associated with survival. Use of tiling-path aCGH prompted re-evaluation of the hypothetical pathways of breast carcinogenesis. ILCs have the simplest changes on 16q and probably diverge from the IDC lineage close to the stage of 16q loss. Higher-grade IDCs probably develop from low-grade lesions in most cases, but there remains evidence that some GII/GIII IDCs arise without a GI precursor. 相似文献
16.
Hackett CS Hodgson JG Law ME Fridlyand J Osoegawa K de Jong PJ Nowak NJ Pinkel D Albertson DG Jain A Jenkins R Gray JW Weiss WA 《Cancer research》2003,63(17):5266-5273
Neuroblastoma, the third most common tumor of childhood, is a complex disease in which few genetic mutations have been identified.Mice expressing a human MYCN oncogene driven by the rat tyrosine hydroxylase promoter (TH-MYCN) represent an animal model for this disorder. We performed microarray-based comparative genomic hybridization analysis on murine tumors, identifying gains on chromosomes 1, 3, 11, 14, 17, and 18 and losses on chromosomes 5, 9, and 16. Fluorescence in situ hybridization analysis confirmed an amplicon on chromosome 18 as the site of TH-MYCN transgene integration. Selected tumors with localized gains of chromosome 11 delineate a 15-Mb region orthologous to human chromosome 17q and help to narrow the minimal region gained in human tumors. We observed clustered loss of chromosomes 5, 9, and 16, orthologous to a similar pattern of combined loss of chromosomes 3p, 4p, and 11q in human tumors. These data demonstrate conservation of many genetic changes in murine and human neuroblastoma and suggest that further delineation of genetic abnormalities in murine tumors may identify genes important in human disease. 相似文献
17.
Lockwood WW Coe BP Williams AC MacAulay C Lam WL 《International journal of cancer. Journal international du cancer》2007,120(2):436-443
Cervical cancer is the second most common malignancy in women worldwide, with high risk subtypes of human papillomavirus (HPV) constituting the major etiological agent. However, only a small percentage of women infected by the virus develop disease, suggesting that additional host genetic alterations are necessary for disease progression. In this study we examined the genomes of a panel of commonly used model cervical cancer cell lines using a recently developed whole genome tiling path array for CGH analysis. Detailed analysis of genomic profiles enabled the detection of many novel aberrations, which may have been missed by conventional cytogenetic methods. In total, 27 minimal regions of recurrent copy number alteration were identified that are potentially involved in tumorigenesis. Interestingly, fine mapping of the 3q gain, which is associated with the progression of precursor lesions to invasive cervical cancer, identified a minimal region of alteration harboring genes distinct from previous candidates. Novel regions of gene amplification, including the coamplification of both the Birc and MMP gene clusters on 11q22, were also evident. Lastly, characterization of genomic structure at sites of HPV integration identified the copy number gain of host cellular sequences between the viral-host genomic boundaries in both SiHa and SW756, suggesting a direct role for HPV integration in the development of genetic abnormalities that initiate cervical cancer. This work represents the highest resolution look at a cervical cancer genome to date and offers definitive characterization of the alteration status of these cancer cell lines. 相似文献
18.
High-resolution analysis of gene copy number alterations in human prostate cancer using CGH on cDNA microarrays: impact of copy number on gene expression 总被引:4,自引:0,他引:4
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Wolf M Mousses S Hautaniemi S Karhu R Huusko P Allinen M Elkahloun A Monni O Chen Y Kallioniemi A Kallioniemi OP 《Neoplasia (New York, N.Y.)》2004,6(3):240-247
19.
Origins and selection of p53 mutations in lung carcinogenesis 总被引:3,自引:0,他引:3
Molecular epidemiologists usually consider the spectrum of p53 mutations found in human tumors to be a signature of the corresponding environmental carcinogen(s). In lung cancer, this signature is the spectrum of G --> T transversions, presumably induced by polycyclic aromatic hydrocarbons (PAH) from cigarette smoke. What complicates the situation, however, is that in the p53 gene the same codons are preferential targets for not only mutagenesis but also tumorigenic selection. In this review, we compare the G --> T spectra induced by PAH o-quinones and diol epoxides with those in lung cancer and show that the main "shaper" of the latter is selection, not mutagenesis. In addition, we propose the approach that allows to distinguish selection and mutagenesis components of the p53 spectra and, therefore, to test the suspect carcinogens for their "in vivo" mutagenic involvement. Collectively, the reviewed basic premises, concepts and data are consistent with the increasing recognition of environmental cancer risk conditions as selecting rather than inducing tumorigenic mutations. 相似文献
20.
The members of the p38 subfamily of Mitogen-Activated Protein Kinases (MAPKs) are a versatile group of proteins, that function as signal transducers involved in key cellular functions. Initially, p38 MAPKs were associated with inflammatory and cellular stress responses and, as such, p38 has been an important target for anti-inflammatory therapies. Recently, increasing evidence has directly implicated p38 MAPKs in processes essential for cell development, transformation and tumorogenesis, namely: proliferation, differentiation, apoptosis, invasion and metastasis. These features make p38 MAPKs potential targets for future anti-neoplastic therapies. 相似文献