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)

In this study nine colorectal cancer cell lines were analysed by 10K SNP-arrays and spectral karyotyping (SKY). Complex chromosomal alterations and breakpoints of deleted or translocated fragments found by SKY could further be characterized by SNP-array analysis. Interestingly many monoallelic regions identified by SNP-array analysis display no copy number alterations, representing uniparental disomy (UPD). It was demonstrated that UPD seems to be involved in activation of early-acting tumor suppressor genes in MSS- (APC, CDKN2A) and MSI- (MLH1, MSH2, APC, CDKN2A) colorectal cancer cell lines. Genes involved later on in the adenoma-carcinoma sequence (i.e. TP53/SMAD4) were not found to be inactivated by UPD. Furthermore, identified amplified monoallelic regions may include oncogenes activated by allele-specific-amplification (i.e. Cyclin D1). However, at present, the majority of the monoallelic regions located in the present study have not yet been associated with known tumor suppressor genes and oncogenes. Further studies are warranted to identify relevant genes in the respective regions and to further verify the results presented here.
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PMID:SNP-Array genotyping and spectral karyotyping reveal uniparental disomy as early mutational event in MSS- and MSI-colorectal cancer cell lines. 1800 Mar 73

Werner syndrome is a premature aging syndrome characterized by early onset of cancer and abnormal cellular metabolism of glycosaminoglycan. The WRN helicase plays an important role in the maintenance of telomere function. WRN promoter methylation and gene silencing are common in colorectal cancer with the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and mucinous tumors. However, no study has examined the relationship between mucinous differentiation, WRN methylation, CIMP and MSI in colorectal cancer. Utilizing 903 population-based colorectal cancers and real-time PCR (MethyLight), we quantified DNA methylation in WRN and eight other promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) known to be specific for CIMP. Supporting WRN as a good CIMP marker, WRN methylation was correlated well with CIMP-high diagnosis (> or =6/8 methylated promoters), demonstrating 89% sensitivity and 81% specificity. WRN methylation was associated with the presence of any mucinous component and > or =50% mucinous component (P<0.0001). Because both MSI and CIMP were associated with mucinous tumors and WRN methylation, we stratified tumors into 9 MSI/CIMP subtypes, to examine whether the relationship between WRN methylation and mucin still persisted. In each MSI/CIMP subtype, tumors with mucinous component were persistently more common in WRN-methylated tumors than WRN-unmethylated tumors (P=0.004). No relations of WRN methylation with other variables (age, sex, tumor location, poor differentiation, signet ring cells, lymphocytic reactions, KRAS, BRAF, p53, p21 or 18q loss of heterozygosity) persisted after tumors were stratified by CIMP status. In conclusion, WRN methylation is associated with mucinous differentiation independent of CIMP and MSI status. Our data suggest a possible role of WRN methylation in mucinous differentiation, and may provide explanation to the enigmatic association between mucin and MSI/CIMP.
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PMID:WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer. 1808 50

Insulin-like growth factor binding protein 3 (IGFBP3), which is induced by wild-type p53, regulates IGF and interacts with the TGF-beta pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight), we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1). IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41) than in MSI-high CIMP-high (49% = 44/90, P < .0001), MSI-high non-CIMP-high (17% = 6/36, P < .0001), and non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001). Among CIMP-high tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001), but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02). In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, and this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/CIMP), single molecular events (e.g., IGFBP3 methylation, TP53 mutation, and TGFBR2 mutation), and the related pathways.
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PMID:IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53. 1808 16

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.
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PMID:PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. 1851 90

Our understanding of somatic alterations in colon cancer has evolved from a concept of a series of events taking place in a single sequence to a recognition of multiple pathways. An oncogenetic tree is a model intended to describe the pathways and sequence of somatic alterations in carcinogenesis without assuming that tumors will fall in mutually exclusive categories. We applied this model to data on colon tumor somatic alterations. An oncogenetic tree model was built using data on mutations of TP53, KRAS2, APC, and BRAF genes, methylation at CpG sites of MLH1 and TP16 genes, methylation in tumor (MINT) markers, and microsatellite instability (MSI) for 971 colon tumors from a population-based series. Oncogenetic tree analysis resulted in a reproducible tree with three branches. The model represents methylation of MINT markers as initiating a branch and predisposing to MSI, methylation of MHL1 and TP16, and BRAF mutation. APC mutation is the first alteration in an independent branch and is followed by TP53 mutation. KRAS2 mutation was placed a third independent branch, implying that it neither depends on, nor predisposes to, the other alterations. Individual tumors were observed to have alteration patterns representing every combination of one, two, or all three branches. The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis.
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PMID:Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors. 1876 47

Apoptosis is essential for complex multicellular organisms and its failure is associated with genome instability and cancer. Interactions between apoptosis and genome-maintenance mechanisms have been extensively documented and include transactivation-independent and -dependent functions, in which the tumor-suppressor protein p53 works as a 'molecular node' in the DNA-damage response. Although apoptosis and genome stability have been identified as ancient pathways in eukaryote phylogeny, the biological evolution underlying the emergence of an integrated system remains largely unknown. Here, using computational methods, we reconstruct the evolutionary scenario that linked apoptosis with genome stability pathways in a functional human gene/protein association network. We found that the entanglement of DNA repair, chromosome stability and apoptosis gene networks appears with the caspase gene family and the antiapoptotic gene BCL2. Also, several critical nodes that entangle apoptosis and genome stability are cancer genes (e.g. ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6 and TP53), although their orthologs have arisen in different points of evolution. Our results demonstrate how genome stability and apoptosis were co-opted during evolution recruiting genes that merge both systems. We also provide several examples to exploit this evolutionary platform, where we have judiciously extended information on gene essentiality inferred from model organisms to human.
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PMID:Evolutionary origins of human apoptosis and genome-stability gene networks. 1883 73

Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play an important role in disseminating clinical classification of variants. The IARC Working Group on Unclassified Genetic Variants has proposed a new system of five classes of variants in cancer susceptibility genes. However, standards are lacking for reporting and analyzing the multiple data types that assist in classifying variants. By adhering to standards of transparency and consistency in the curation and annotation of data, LSDBs can be critical for organizing our understanding of how genetic variation relates to disease. In this article we discuss how LSDBs can accomplish these goals, using existing databases for BRCA1, BRCA2, MSH2, MLH1, TP53, and CDKN2A to illustrate the progress and remaining challenges in this field. We recommend that: 1) LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel. 2) The system used to classify variants should be standardized. The Working Group encourages use of the five class system described in this issue by Plon and colleagues. 3) Evidence that supports a conclusion should be reported in the database, including sources and criteria used for assignment. 4) Variants should only be classified as pathogenic if more than one type of evidence has been considered. 5) All instances of all variants should be recorded.
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PMID:Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. 1895 38

Ovarian cancer shows considerable variability in its chemoresponse, however, the prospect of individualized medicine holds high hopes for improving patient survival. The influence of interindividual genomic polymorphisms on drug response (pharmacogenomics) is well established, and a variety of candidate loci in ovarian tumors have been identified, including ERCC1, ABCB1 and p53 variants. Recently pharmacoepigenomic modulators of key genes and pathways, such as promoter methylation (MLH1 and BRCA1 genes) and microRNA regulation (PTEN/AKT and NF-kappaB pathways) have been implicated in ovarian cancer chemoresponse. Epigenomic studies have until now mainly focused on tumor-specific changes, although germ-line epigenetic change may also be of importance. However, assessing the relevance of these potential pharmaco(epi)genomic biomarkers in clinical trials requires well powered studies in homogeneous populations, with independent validation sets, to distinguish real associations from false-positives. In addition, the selection of one gene or locus as having sufficient phenotypic effect to impact on clinical outcome may be an oversimplification. Integrated approaches that identify stable pharmacogenomic and epigenomic patterns and their relationship with expression patterns and gene function will be increasingly necessary.
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PMID:Pharmaco(epi)genomics in ovarian cancer. 1907 41

Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.
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PMID:Genome-wide expression profile of sporadic gastric cancers with microsatellite instability. 1908 Dec 45

JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize beta-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (>/=2 chromosomal segments with LOH; P < .0001), nuclear beta-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, beta-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation.
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PMID:JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype. 1910 35


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