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)

DNA methylation in CpG islands is associated with transcriptional silencing. Accurate determination of cytosine methylation status in promoter CpG dinucleotides may provide diagnostic and prognostic value for human cancers. We have developed a quantitative PCR/LDR/Universal Array assay that allows parallel evaluation of methylation status of 75 CpG dinucleotides in the promoter regions of 15 tumor suppressor genes (CDKN2B, CDKN2A, CDKN2D, CDKN1A, CDKN1B, TP53, BRCA1, TIMP3, APC, RASSF1, CDH1, MGMT, DAPK1, GSTP1, and RARB). When compared with an independent pyrosequencing method at a single promoter, the two approaches gave good correlation. In a study using 15 promoter regions and seven blinded tumor cell lines, our technology was capable of distinguishing methylation profiles that identified cancer cell lines derived from the same origins. Preliminary studies using 96 colorectal tumor samples and 73 matched normal tissues indicated CpG methylation is a gene-specific and nonrandom event in colon cancer. This new approach is suitable for clinical applications where sample quantity and purity can be limiting factors.
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PMID:Multiplexed profiling of candidate genes for CpG island methylation status using a flexible PCR/LDR/Universal Array assay. 1636 45

We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.
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PMID:Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis. 1737 10

Previously, we have developed a unique in vitro LNCaP cell model, which includes androgen-dependent (LNCaP-C33), androgen-independent (LNCaP-C81) and an intermediate phenotype (LNCaP-C51) cell lines resembling the stages of prostate cancer progression to hormone independence. This model is advantageous in overcoming the heterogeneity associated with the prostate cancer up to a certain extent. We characterized and compared the gene expression profiles in LNCaP-C33 (androgen-dependent) and LNCaP-C81 (androgen-independent) cells using Affymetrix GeneChip array analyses. Multiple genes were identified exhibiting differential expression during androgen-independent progression. Among the important genes upregulated in androgen-independent cells were PCDH7, TPTE, TSPY, EPHA3, HGF, MET, EGF, TEM8, etc., whereas many candidate tumor suppressor genes (HTATIP2, CDKN2A, CDKN2B, CDKN1C, TP53, TP73, ICAM1, SOCS1/2, SPRY2, PPP2CA, PPP3CA, etc.) were decreased. Pathway prediction analysis identified important gene networks associated with growth-promoting and apoptotic signaling that were perturbed during androgen-independent progression. Further investigation of one of the genes, PPP2CA, which encodes the catalytic subunit of a serine phosphatase PP2A, a potent tumor suppressor, revealed that its expression was decreased in prostate cancer compared to adjacent normal/benign tissue. Furthermore, the downregulated expression of PPP2CA was significantly correlated with tumor stage and Gleason grade. Future studies on the identified differentially expressed genes and signaling pathways may be helpful in understanding the biology of prostate cancer progression and prove useful in developing novel prognostic biomarkers and therapy for androgen-refractory prostate cancer.
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PMID:Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. 1797 48

Fibrolamellar carcinomas have a unique predilection for younger individuals and arise in livers without recognizable liver disease. In contrast to typical hepatocellular carcinomas, fibrolamellar carcinomas show few chromosomal changes and lack mutation in key genes such as TP53 and CTNNB1. Epigenetic instability, manifesting as methylation of important tumor suppressor gene promoters, has not been investigated in fibrolamellar carcinomas. Thus, the methylation status of 11 tumor suppressor gene promoters was investigated using methylation-specific PCR: RASSF1, CDH1, CDKN2B, HPP1, CDKN2A, GSTP1, P16, RARA, FLJ13081, SOCS1, and TP53. Nine fibrolamellar carcinomas were studied including primary tumors (N=5) and metastatic deposits (N=4) along with control groups of typical hepatocellular carcinoma arising in livers with (N=21) and without cirrhosis (N=10). In fibrolamellar carcinomas, RASSF1A and CDH1 (e-cadherin) were the most commonly methylated genes with 80-100% of tumors methylated. However, overall fibrolamellar carcinomas showed low levels of methylation with no differences between fibrolamellar carcinomas and their paired normal livers. However, fibrolamellar carcinomas showed significantly less methylation than hepatocellular carcinomas that arose in the background of viral cirrhosis. Overall, methylation was most strongly linked to viral cirrhosis. In conclusion, fibrolamellar carcinoma shows low levels of methylation. In contrast, higher levels of promoter methylation are associated with hepatocellular carcinomas that arise in the setting of viral induced cirrhosis.
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PMID:Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas. 1826 82

Actinic keratosis (AK) is a well-established pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). We investigated the involvement of the CDKN2A, CDKN2B and p53 genes in AK and in the progression of AK to SCC. Mutational analysis on exons 1a, 1b and 2 of the CDKN2A locus and exon 1 of the CDKN2B locus as well as allelic imbalance was performed in 26 AK specimens. Expression levels of the genes p14(ARF), p15(INK4b), p16(INK4a) and p53 were examined in 16 AKs and 12 SCCs by real-time RT-PCR. A previously described polymorphism of p16(INK4a) (Ala148Thr) was detected at an allelic frequency of 12%. Six samples carried novel mutations at codon 71 of the CDKN2A locus and one sample presented an additional mutation at codon 65. Two AK samples carried a not-previously described non-UV type missense mutation at codon 184 (Val184Glu) of exon 1b in the p14(ARF) gene. Regarding the CDKN2B locus a new mutation at codon 50 (Ala50Thr) and another at codon 24 (Arg24Arg), were detected. Microsatellite instability (MSI) was found in 15% of AKs in at least one marker, indicating that genetic instability has some implication in the development of AK. Down-regulation of p16(INK4a) and p53 mRNA levels was noted in SCC compared to AK. TSGs expression levels in sun-exposed morphologically normal-appearing skin, suggests that abnormal growth stimuli might exist in these tissues as well. Furthermore, we suggest a possible role of p15(INK4b), independently from the intracellular pathway mediated by p16(INK4a), and of p14(ARF) in AK development, as well as in the progression of AK to SCC. The deregulation of the expression profiles of the CDKN2A, CDKN2B and p53 genes may, independently of mutations and LOH at 9p21, play a significant role in AK and progression of AK to SCC.
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PMID:Genomic instability, mutations and expression analysis of the tumour suppressor genes p14(ARF), p15(INK4b), p16(INK4a) and p53 in actinic keratosis. 1833 79

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

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.
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PMID:Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. 1851 75

Multiple myeloma (MM) is an incurable plasma cell neoplasm. Pathogenesis involves upregulation of D-type cyclins and activation of oncogenes, but little is known about the role of tumor suppressor genes. Gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation. Various approaches have been used to elucidate the role of gene hypermethylation in MM, including a candidate gene approach, microarray approach for genes upregulated by hypomethylating agents, and a cancer pathway approach, which enables a comprehensive picture of the involvement of multiple tumor suppressor genes in MM. Based on the cancer pathway approach, the following data on the involvement of cell cycle control, intrinsic tumor suppressor, and cell signaling were derived. First, among the INK4 and CIP/KIP families of cyclin-dependent kinase inhibitors, only CDKN2B and CDKN2A are frequently hypermethylated. Second, methylation of SHP1 and soluble Wnt inhibitors is associated with constitutive activation of JAK/STAT and Wnt signaling. Importantly, downregulation of the signaling pathways can be restored by demethylation and re-expression of SHP1 and soluble Wnt inhibitors, which is potentially important therapeutically. Third, of the tumor suppressor genes involved in the DAPK/P14/HDM2/P53/Apaf-1 pathway, only DAPK is frequently methylated, which appeared to be an adverse prognostic factor to survival. Lastly, apart from being implicated in the progression from monoclonal gammopathy of unknown significance to MM, aberrant gene promoter methylation might also account for late disease progression in MM. Future studies are needed to delineate the biologic consequence of gene hypermethylation, the prognostic effect of gene methylation, and the possibility of hypomethylation therapy.
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PMID:Gene hypermethylation in multiple myeloma: lessons from a cancer pathway approach. 1906 97

The t(11;14)(q13;q32) is the hallmark of mantle cell lymphoma (MCL). Additional genetic alterations occur in the majority of cases. This study aimed to design a polymerase chain reaction (PCR) assay to determine the incidence and relevance of recurrent gene copy number aberrations in this disease. Forty-two MCL cases with frozen- or paraffin-embedded (FFPE) tissues were selected. Three different quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) assays were designed to simultaneously analyse eight genes (CDKN2A, RB1, ATM, CDK2, TP53, MYC, CDKN1B, MDM2), to analyse the 9p21 locus (CDKN2A/CDKN2B) and FFPE tissues. Gains of MYC, CDK2, CDKN1B, and MDM2 were observed in 10% of cases. Losses of RB1, CDKN2A, ATM or TP53 were observed in 38%, 31%, 24% and 10% of cases, respectively. Analysis of the 9p21 locus indicated that, in most cases, tumours displayed a complete inactivation of p14(ARF)/p15I(NK4B)/p16I(NK4A). CDKN2A and MYC aberrations were associated with a high MCL international prognostic index (MIPI). CDK2/MDM2 gains and CDKN2A/TP53 losses correlated with an unfavourable outcome. PCR experiments with frozen and FFPE-tissues indicated that our approach is valid in a routine diagnostic setting, providing a powerful tool that could be used for patient stratification in combination with MIPI in future clinical trials.
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PMID:Detection of gene copy number aberrations in mantle cell lymphoma by a single quantitative multiplex PCR assay: clinicopathological relevance and prognosis value. 1959 47

Glioblastoma Multiforme (GBM) is a malignant brain cancer that develops after accumulating genomic DNA damage that often includes gene amplifications and/or deletions. These copy number changes can be a critical step in brain tumor development. To evaluate glioblastoma genomic copy number changes, we determined the genome-wide copy number alterations in 31 GBMs. Illumina Bead Arrays were used to assay 22 GBMs and Digital Karyotyping was used on 8 GBM cell lines and one primary sample. The common amplifications we observed for all 31 samples was GLI/CDK4 (22.6%), MDM2 (12.9%) and PIK3C2B/MDM4 (12.9%). In the 22 GBM tumors, EGFR was amplified in 22.7% of surgical biopsies. The most common homozygously deleted region contained CDKN2A/CDKN2B (p15 and p16) occurring in 29% of cases. This data was compiled and compared to published array CGH studies of 456 cases of GBMs. Pooling our Illumina data with published studies yielded these average amplification rates: EGFR-35.7%, GLI/CDK4-13.4%, MDM2-9.2%, PIK3C2B/MDM4-7.7%, and PDGFRA-7.7%. The CDKN2A/CDKN2B locus was deleted in 46.4% of the combined cases. This study provides a larger assessment of amplifications and deletions in glioblastoma patient populations and shows that several different copy number technologies can produce similar results. The main pathways known to be involved in GBM tumor formation such as p53 control, growth signaling, and cell cycle control are all represented by amplifications or deletions of critical pathway genes. This information is potentially important for formulating targeted therapy in glioblastoma and for planning genomic studies.
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PMID:A survey of glioblastoma genomic amplifications and deletions. 1960 42


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