Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is a leading cause of cancer-death among women, where the clinicopathological features of tumors are used to prognosticate and guide therapy. DNA copy number alterations (CNAs), which occur frequently in breast cancer and define key pathogenetic events, are also potentially useful prognostic or predictive factors. Here, we report a genome-wide array-based comparative genomic hybridization (array CGH) survey of CNAs in 89 breast tumors from a patient cohort with locally advanced disease. Statistical analysis links distinct cytoband loci harboring CNAs to specific clinicopathological parameters, including tumor grade, estrogen receptor status, presence of TP53 mutation, and overall survival. Notably, distinct spectra of CNAs also underlie the different subtypes of breast cancer recently defined by expression-profiling, implying these subtypes develop along distinct genetic pathways. In addition, higher numbers of gains/losses are associated with the "basal-like" tumor subtype, while high-level DNA amplification is more frequent in "luminal-B" subtype tumors, suggesting also that distinct mechanisms of genomic instability might underlie their pathogenesis. The identified CNAs may provide a basis for improved patient prognostication, as well as a starting point to define important genes to further our understanding of the pathobiology of breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat
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PMID:Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. 1689 46

The transcription factor ZNF217 is often amplified in ovarian cancer, but its role in neoplastic progression is unknown. We introduced ZNF217-HA by adenoviral and retroviral infection into normal human ovarian surface epithelial cells (OSE), i.e., the source of ovarian cancer, and into SV40 Tag/tag expressing, p53/pRB-deficient OSE with extended but finite life spans (IOSE). In OSE, ZNF217-HA reduced cell-substratum adhesion and accelerated loss of senescent cells, but caused no obvious proneoplastic changes. In contrast, ZNF217-HA transduction into IOSE yielded two permanent lines, I-80RZ and I-144RZ, which exhibited telomerase activity, stable telomere lengths, anchorage independence and reduced serum dependence, but were not tumorigenic in SCID mice. This immortalization required short-term EGF treatment near the time of crisis. The permanent lines were EGF-independent, but ZNF217-dependent since siRNA to ZNF217 inhibited anchorage independence and arrested growth. Array CGH revealed genomic changes resembling those of ovarian carcinomas, such as amplicons at 3q and 20q, and deletions at 4q and 18, associated with underexpressed annexin A10, N-cadherin, desmocollin 3 and PAI-2, which have been reported as tumor suppressors. The lines overexpressed EEF1A2, SMARA3 and STAT1 and underexpressed other oncogenes, tumor suppressors and extracellular matrix/adhesion genes. The results implicate ZNF217 as an ovarian oncogene, which is detrimental to senescing normal OSE cells but contributes to neoplastic progression in OSE with inactivated p53/RB. The resemblance of the genomic changes in the ZNF217-overexpressing lines to ovarian carcinomas provides a unique model to investigate interrelationships between these changes and ovarian neoplastic phenotypes.
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PMID:Multiple roles of the candidate oncogene ZNF217 in ovarian epithelial neoplastic progression. 1726 44

We describe two newly established malignant mesothelioma (MM) cell lines derived from a pleural effusion of a male. One cell line, designated as MM-Z03E, reveals an epithelioid cobblestone morphology, while the second one, designated as MM-Z03S and subcloned after in vivo selection, exhibits a sarcomatoid storiform growth pattern. Both cell lines showed the immunologic profile characteristic for MM (i.e., expression of cytokeratin, CK18, calretinin, and vimentin in both phenotypes). Cytogenetics, multicolor fluorescence in situ hybridization, comparative genomic hybridization, and oligonucleotide array CGH were performed on both cell lines. Aberrations shared by both cell lines included chromosomal losses of 1q34 approximately qter, 4, 9p, 10p, 13, 14, 16q, 18, and 22, as well as a complex structural aberration involving chromosome 17. Aberrations exclusive to MM-Z03E included gains of 3q11q27 and 5p, while gain of 9q and losses of 3q27qter, 11q, and 18 in MM-Z03S were exclusive to MM-Z03E. Both cell lines were able to develop solid transplant tumors in nude mice within 16 weeks, and immunophenotyping of tumor xenografts revealed an overall retained expression profile of the markers used. Remarkably, one xenograft from MM-Z03E revealed overexpression of p53 and widely invasive growth. In conclusion, both cell lines are useful in vivo and in vitro model systems to study the underlying genetic mechanisms of biphasic differentiation in MM, which can be of certain value considering the increasing relevance of assessing MM tumor biology for the clinical management of this disease.
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PMID:Establishment and characterization of two distinct malignant mesothelioma cell lines with common clonal origin. 1757 62

About 5% of gliomas occur in a familial context, which suggests a genetic origin, but the predisposing molecular factors remain unknown in most cases. A series of nine familial gliomas were characterized with 1-megabase resolution BAC array-based comparative genomic hybridization (aCGH) together with germline sequence analysis of TP53. This series was compared with a literature series of familial gliomas and a personal series of sporadic gliomas, analyzed by chromosome CGH and aCGH, respectively. No significant difference was noted between the three populations in terms of clinical characteristics, pathologic features, and the most frequent chromosomal alterations, including loss of 1p, 10p, 10q, 13q, and 19q, and gain of 7p, 7q, 16p, 18q, 19p, 19q, 20p, and 22q. However, a genomic region located in 6q was more frequently gained in our series of familial as compared to sporadic gliomas (P=0.028). A germline TP53 mutation was observed in 1/9 cases, which suggests Li-Fraumeni syndrome. Interestingly, the Pro allele in the codon 72 of TP53 was observed in 5/9 tumors. Although familial and sporadic gliomas share very similar cytogenetic quantitative patterns, aCGH is a promising technique for the detection of small genomic differences of potential significance.
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PMID:Tumor genomic profiling and TP53 germline mutation analysis of first-degree relative familial gliomas. 1765 54

We described a rare malignant fibrous histiocytoma of the parotid gland (MFH) in a 63-year-old woman. During six months the tumour size became 10 cm in diameter with skin ulceration. The tumour was examined morphologically, by immunohistochemistry and molecular biology methods - FASAY and CGH. The histology revealed a storiform-pleomorphic type of MFH with high mitotic rate. The FASAY method identified a non-mutated p53 gene. The chromosomal changes were identified by the CGH method and 6 cytogenetic changes were found in the tumour cells (deletions at 8p12-p22, 13q32-qter, 14q24-qter, and gains of chromosomal material at 5p, 8q12-q23, and Xq25-qter). The patient died shortly after the beginning of chemotherapy. Autopsy revealed brain and cerebellar haemorrhage. No other tumour foci were proved. In view of short course of disease we lack the data about the influence of the non-mutated p53 gene on the prognosis and therapy.
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PMID:Malignant fibrous histiocytoma of the parotid gland. 1818 22

The incidence of salivary gland tumor in Poland is growing in the last two decades. Simultaneously a progress in understanding the genetic mechanisms of formation of this tumor was achieved by detecting several genes like PLAG1 involved in its pathogenesis. In this study we perform a whole genome, CGH analysis with the aim to identify recurrent, chromosomal copy number changes possibly indicating novel tumor suppressor gene or oncogene loci. 29 salivary tumor samples: Cystadenolymphoma-warthin (15) and adenoma polymorphum (14) located in the parotid (27) and submandibular gland (2) were collected and CGH was performed. The established copy number profiles were compared in order to asses the smallest common region of gains and losses. The delineated regions were further analyzed with the UCSC Genome Browser on Human Mar. 2006 Assembly to asses their gene content. Altogether, salivary gland tumors presented a different aberration pattern than these reported for head and neck squamous cell carcinoma (HNSCC) but no significant differences were observed between Warthin and adenoma polymorphum tumors. Moreover, several potential tumor suppressor genes and oncogenes were identified in the smallest, common altered regions. We show a frequent deletion of the harakiri gene (12q24.2) in 12/29 tumors and TP53 gene (17p13.1) in 11/29 tumors as potential tumor suppressors in salivary gland cancers. Besides, we detected a frequent amplification of the 13q22.1-22.2 region in 13/29 cases harboring the KLF5 and KLF12 genes. KLF5 regulates the expression of survivin, an oncogene widely expressed in the majority of human cancers. The observed alterations may indicate important genetic events in the formation of salivary gland tumors. Especially the amplification in 13q may be a mechanism contributing to the expression of survivin and tumor progression.
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PMID:Chromosomal gains and losses indicate oncogene and tumor suppressor gene candidates in salivary gland tumors. 1819 Feb 42

Adenoid cystic carcinoma (ACC) is a rare but distinctive tumor. Oligonucleotide array comparative genomic hybridization has been applied for cataloging genomic copy number alterations (CNAs) in 17 frozen salivary or bronchial tumors. Only four whole chromosome CNAs were found, and most cases had 2-4 segmental CNAs. No high level amplification was observed. There were recurrent gains at 7p15.2, 17q21-25, and 22q11-13, and recurrent losses at 1p35, 6q22-25, 8q12-13, 9p21, 12q12-13, and 17p11-13. The minimal region of gain at 7p15.2 contained the HOXA cluster. The minimal common regions of deletions contained the CDKN2A/CDKN2B, TP53, and LIMA1 tumor suppressor genes. The recurrent deletion at 8q12.3-13.1 contained no straightforward tumor suppressor gene, but the MIRN124A2 microRNA gene, whose product regulates MMP2 and CDK6. Among unique CNAs, gains harbored CCND1, KIT/PDGFRA/KDR, MDM2, and JAK2. The CNAs involving CCND1, MDM2, KIT, CDKN2A/2B, and TP53 were validated by FISH and/or multiplex ligation-dependent probe amplification. Although most tumors overexpressed cyclin D1 compared with surrounding glands, the only case to overexpress MDM2 had the corresponding CNA. In conclusion, our report suggests that ACC is characterized by a relatively low level of structural complexity. Array CGH and immunohistochemical data implicate MDM2 as the oncogene targeted at 12q15. The gain at 4q12 warrants further exploration as it contains a cluster of receptor kinase genes (KIT/PDGFRA/KDR), whose products can be responsive to specific therapies.
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PMID:High-resolution array comparative genomic hybridization analysis of human bronchial and salivary adenoid cystic carcinoma. 1833 73

Carcinosarcomas are malignant tumors with a mixture of carcinomatous and differentiated sarcomatous elements. We investigate the morphology, immunohistochemistry, and comparative genomic hybridization analysis of 3 mixed squamous carcinoma and osteosarcoma of the lung. All patients were male and their ages were 72, 43, and 58 years. The sizes of the neoplasms were 7, 5, and 5 cm in maximum diameter, respectively. Two patients died of the disease 9 and 14 months after surgery; and one is alive 6 months later. By light microscopy, all cases had both squamous and osteosarcomatous structures. Immunohistochemistry was positive for AE3AE1, p63, 34 E12, CAM 5.2 (2/3 cases), CK-7 (2/3 cases), epithelial membrane antigen, E-cadherin, p53, and carcinogenic embryonic antigen in carcinomatous areas, and for vimentin and CD-68 in sarcomatous component. Areas of transition positive for both cytokeratins and vimentin were seen in all cases. A total of 55 copy number changes were detected with a median of 18 abnormalities per case: 48 gains, 6 losses, and 1 high-level amplification. Chromosome alterations in osteosarcomatous areas were similar to those found in lung metastatic osteosarcoma, comparable to those found in carcinomatous areas and to lung squamous carcinomas. Coincidences between carcinomatous areas and osteosarcomatous zones were found as gains in chromosomes 1q, 3q, 5p, 8q, and 12p. These findings provide arguments that favor a common origin for both types of cells, supported by the mixture of cells, the existence of undifferentiated cells positive to both cytokeratin and vimentin markers, and the CGH overlaps of chromosomal gains between carcinomatous and sarcomatous areas.
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PMID:Primary mixed squamous carcinoma and osteosarcoma (carcinosarcomas) of the lung have a CGH mapping similar to primitive squamous carcinomas and osteosarcomas. 1838 57

Efficacy of camptothecins (CPTs) such as irinotecan has been recognized in chemotherapy of cancers including melanoma. However, the majority of responding patients will gradually acquire drug resistance. Little is known of the genes responsible for the acquired CPT-resistance in cancer. To gain global insight into acquired CPT-resistance, we established irinotecan-resistant clones derived from melanoma cells and compared their whole genomes by high resolution array-CGH. A novel gain at 14q23.2-31.1 was revealed by alignment of whole genome profiles of parental cell line and irinotecan-resistant clones. Further analysis of this amplicon indicates that it encompassed genes involved in DNA repair (RAD51L, MLH3), reactive oxygen species (GPX2, CSTZ1, NGB, RDH11, ZADH1), and transportome (ABCD4, ATP6V1D, SLC10A6). Moreover, losses were also detected at the loci of topoisomerases (TOP1, SPO11, TOP3B) as well as at the loci of genes guarding chromosomal stability (TP53, ZW10, H2AFX, CHK1, CCDN1, MCM5, CENPB, DNMT3B), which would facilitate the development of drug resistance. Furthermore, quantitative real-time PCR demonstrated that mRNA changes of selected novel genes (CENPB, H2AFX, MCM5, ZADH1 and NGB) in irinotecan-resistant clones vs. parental clone were in agreement with array-CGH results. Taken together, our data suggest that genes involved in genome stability may greatly contribute to the development of CPTs-resistance. In addition, genes located at 14q23.3-31.1 would be promising targets to overcome acquired CPT-resistance in melanoma.
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PMID:Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells. 1849 97

The aim of the study was to estimate genetic alterations detected in ovarian cancer cells in correlation with other available parameters of histopathological and clinical character and to find important relations with impacts on the cancer prognosis. Additionally, we wanted to compare methods for evaluating genetic changes. Sixty patients with ovarian cancer were included in the study. The histological type and grade were defined, MIB-1 and p53 were estimated using an immunohistochemical method. For genetic testing, both conventional and molecular methods were applied - direct culture and G-banding technique, FISH method with whole chromosome painting probes, and CGH method. The results were submitted to statistical evaluation, using analysis of variances and chi2 test, with Bonnferroni correlations of the significance level. Numerical and structural aberrations have been detected in more than 63 % examined ovarian cancer cases. Patients with extensive chromosomal rearrangements were significantly younger. Specific genetic alterations, including some rare findings such as deletion 22q in 36 % of all ovarian cancer samples, have been found, together with associations between particular prognostic factors.
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PMID:Chromosomal rearrangements and their relations to histopathological and clinical parameters in epithelial ovarian cancer. 1849 23


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