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 lung cancer, an association was made between drastic clinical response to epidermal growth factor receptor (EGFR) inhibitors and the presence of somatic mutations within the tyrosine kinase domain of the EGFR. In some cases, patients with partial response or disease stabilization do not always have EGFR-mutated tumors. To go further in the characterization of the EGF pathway, we screened EGFR, ERBB2, ERBB3, KRAS, BRAF, and PIK3CA for mutations in 2 groups of White patients with nonsmall cell lung cancer (45 cancers from women and 46 cancers from men). Associations between TP53 mutations, clinicopathologic parameters, and EGF pathway molecular alterations were analyzed. All mutations were exclusive and essentially found in EGFR and KRAS. We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis. On the contrary, KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation. These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. The identification of BAC features in ADC helps clustering patients that are more likely to fit the EGFR-mutated group.
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PMID:Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. 1700 Nov 63

Downregulation of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased ubiquitin-mediated proteasomal degradation in colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of colorectal cancer with extensive promoter methylation, and associated with high degree of microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706 colorectal cancer samples obtained from two large prospective cohorts. Among the 706 tumors, 112 (16%) were CIMP-high tumors with >or=4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231 tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative tumors than p53-positive tumors. When CIMP-high and non-CIMP-high tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in colorectal cancer. These associations are stronger among p53 wild-type tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of colorectal cancer.
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PMID:Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP. 1708 68

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.
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PMID:Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. 1708 37

Colorectal cancer is a disease that originates from the neoplastic transformation of epithelial cells of the colon and rectum, as a result of the accumulation of genetic and epigenetic aberrations. At least four sequential genetic changes, affecting one oncogene (KRAS) and three tumor suppressor genes (APC, SMAD4 and TP53), are required for the development of colorectal cancer. Abundant experimental studies and epidemiological data, as well as several human clinical trials suggest a protective effect of Vitamin D against colon carcinogenesis. Hypercalcemia, a side effect of natural Vitamin D, has currently restricted its therapeutic use; however, the development of new synthetic analogs with reduced hypercalcemic activity is promising for cancer therapy and prevention. Extensive research to elucidate the mechanisms underlying the anti-cancer action of Vitamin D is being undertaken. Understanding the complex molecular and cellular networks induced by Vitamin D or its analogs will improve the use of these compounds for the prevention and treatment of colorectal cancer.
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PMID:Colorectal cancer: potential therapeutic benefits of Vitamin D. 1715 47

Our objective was to study whether products of oxidative stress, such as hydrogen peroxide (H(2)O(2)), trans-2-hexenal, and 4-hydroxy-2-nonenal (HNE), cause DNA damage in genes, relevant for human colon cancer. For this, total DNA damage was measured in primary human colon cells and colon adenoma cells (LT97) using the single-cell gel electrophoresis assay, known as "Comet Assay." APC, KRAS, and TP53 were marked in the comet images using fluorescence in situ hybridization (Comet FISH). The migration of APC, KRAS, or TP53 signals into the comet tails was quantified and compared to total DNA damage. All three substances were clearly genotoxic for APC, KRAS, and TP53 genes and total DNA in both types of cells. In primary colon cells, TP53 gene was more sensitive toward H(2)O(2), trans-2-hexenal, and HNE than total DNA was. In LT97 cells, the TP53 gene was more sensitive only toward trans-2-hexenal and HNE. APC and KRAS genes were more susceptible than total DNA to both lipid peroxidation products but only in primary colon cells. This suggests genotoxic effects of lipid peroxidation products in APC, KRAS, and TP53 genes. In LT97 cells, TP53 was more susceptible than APC and KRAS toward HNE. Based on the reported gatekeeper properties of TP53, which in colon adenoma is frequently altered to yield carcinoma, this implies that HNE is likely to contribute to cancer progression. This new experimental approach facilitates studies on effects of nutrition-related carcinogens in relevant target genes.
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PMID:Comet fluorescence in situ hybridization analysis for oxidative stress-induced DNA damage in colon cancer relevant genes. 1719 41

Although chromosomal instability characterizes the majority of human colorectal cancers, the contribution of genes such as adenomatous polyposis coli (APC), KRAS, and p53 to this form of genetic instability is still under debate. Here, we have assessed chromosomal imbalances in tumors from mouse models of intestinal cancer, namely Apc(+/1638N), Apc(+/1638N)/KRAS(V12G), and Apc(+/1638N)/Tp53-/-, by array comparative genomic hybridization. All intestinal adenomas from Apc(+/1638N) mice displayed chromosomal alterations, thus confirming the presence of a chromosomal instability defect at early stages of the adenoma-carcinoma sequence. Moreover, loss of the Tp53 tumor suppressor gene, but not KRAS oncogenic activation, results in an increase of gains and losses of whole chromosomes in the Apc-mutant genetic background. Comparative analysis of the overall genomic alterations found in mouse intestinal tumors allowed us to identify a subset of loci syntenic with human chromosomal regions (eg, 1p34-p36, 12q24, 9q34, and 22q) frequently gained or lost in familial adenomas and sporadic colorectal cancers. The latter indicate that, during intestinal tumor development, the genetic mechanisms and the underlying functional defects are conserved across species. Hence, our array comparative genomic hybridization analysis of Apc-mutant intestinal tumors allows the definition of minimal aneuploidy regions conserved between mouse and human and likely to encompass rate-limiting genes for intestinal tumor initiation and progression.
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PMID:Aneuploidy arises at early stages of Apc-driven intestinal tumorigenesis and pinpoints conserved chromosomal loci of allelic imbalance between mouse and human. 1720 Feb 9

Despite tremendous effort and progress in the diagnostics of pancreatic cancer with respect to imaging techniques and molecular genetics, only very few patients can be cured by surgery leading to a 5-year survival rate of only 3%. Especially the lack of chemotherapeutical options in this entity requires a better understanding of the molecular mechanisms leading to pancreatic carcinoma growth and progression in order to develop novel treatment regimens. To identify signaling pathways that are critical for this tumor entity, we compared six well-established pancreatic cancer cell lines (Capan-1, Capan-2, HUP-T3, HUP-T4, KCL-MOH, PaTu-8903) with colon cancer cell lines and tumor cell lines of non-epithelial origin by expression profiling. For this purpose we employed Human Genome Focus Arrays representing about 8500 well annotated human genes. We identified 353 genes with significantly high expression in the group of pancreatic carcinomas. Based on Gene Ontology annotations these genes are especially involved in Rho protein signal transduction, proteasome activator activity, cell motility, apoptotic program, and cell-cell adhesion processes indicating these pathways to be interesting candidates for the design of targeted therapies. Most pancreatic carcinomas are characterized by mutations in the TP53 and the KRAS genes and the absence of microsatellite instability, which could also be confirmed for our panel of pancreatic carcinoma cell lines. Looking for individual differences within this group that may be responsible for more or less aggressive behavior, we identified genomic amplifications at the 8q22.1 and the 8q24.22 loci to be associated with enhanced gene transcription. Because we have previously shown that gains of genomic material from the long arm of chromosome 8 have an adverse effect on the outcome of pancreatic carcinoma patients, we conclude that functional analysis of amplified genes at 8q22 and/or 8q24 may lead to an improved understanding of pancreatic carcinoma progression.
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PMID:Expression analysis of pancreatic cancer cell lines reveals association of enhanced gene transcription and genomic amplifications at the 8q22.1 and 8q24.22 loci. 1720 80

Cytoplasmic mislocalization of p27 (CDKN1B/KIP1) is caused by activated AKT1 and has been associated with poor prognosis in various cancers. CIMP in colorectal cancer is characterized by extensive promoter methylation and is associated with MSI-MSI-H and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in 8 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) in 853 colorectal cancer samples obtained from 2 large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 (P < .0001), CIMP-high (P < .0001), MSI-H (P < .0001), and BRAF mutations (P < .0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS/BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.
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PMID:Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype. 1723 30

The transforming growth factor-beta receptor type 2 gene (TGFBR2) is mutated in most microsatellite instability-high (MSI-H) colorectal cancers. Promoter methylation of RUNX3 (runt-related transcription factor 3; encoding a transcription factor downstream of the TGF-beta pathway) is observed in colorectal cancer with CpG island methylator phenotype (CIMP), which is characterized by extensive promoter methylation and is associated with MSI-H and BRAF mutations. However, no study to date has examined interrelationship between TGFBR2 mutation, RUNX3 methylation, and CIMP in colorectal cancer. Using 144 MSI-H colorectal cancers derived from 2 large prospective cohort studies, we analyzed a mononucleotide repeat of TGFBR2 and quantified DNA methylation (by MethyLight technology) in 8 CIMP-specific promoters (RUNX3, CACNA1G [calcium channel, voltage-dependent, T type alpha-1G subunit], CDKN2A [p16], CRABP1 [cellular retinoic acid binding protein 1], IGF2 [insulin-like growth factor 2], MLH1, NEUROG1 [neurogenin 1], and SOCS1 [suppressor of cytokine signaling 1]). Among the 144 MSI-H tumors, the presence of TGFBR2 mutation (overall 72% frequency) was correlated positively with CIMP-high (with >/=6/8 methylated promoters; P < .0001), RUNX3 methylation (P = .0004), BRAF mutation (P = .0006), and right colon (P = .05); inversely with KRAS mutation (P = .006); but not significantly with sex, tumor differentiation, and p53 status (assessed by immunohistochemistry). After stratification by sex, location, tumor differentiation, RUNX3 status, KRAS/BRAF status, or p53 status, CIMP-high was persistently correlated with TGFBR2 mutation. In contrast, RUNX3, KRAS, or BRAF status was no longer correlated with TGFBR2 mutation after stratification by CIMP status. In conclusion, TGFBR2 mutation is associated with CIMP-high and indirectly with RUNX3 methylation. Our findings emphasize the importance of analyzing global epigenomic status (for which CIMP status is a surrogate marker) when correlating a single epigenetic event (eg, RUNX3 methylation) with any other molecular or clinicopathologic variables.
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PMID:TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer. 1727 Feb 39

Biphasic pulmonary blastoma is a rare lung tumor with epithelial and mesenchymal components. Genetic alterations in this tumor are largely unknown, except for the presence of beta-catenin and p53 mutations and the absence of KRAS mutation. To understand the molecular process of histogenesis of this tumor, a whole genome allelic imbalance (AI) scanning using a high-resolution single nucleotide polymorphism array as well as mutational analysis of the p53, EGFR, KRAS and beta-catenin genes were performed against the epithelial and mesenchymal components in the primary tumor and a metastatic tumor in a case of pulmonary blastoma. AI at chromosome regions 14q24-q32 and 17p11-p13 and beta-catenin mutation were commonly detected in all tumors. On the other hand, AI at chromosome regions 3p11-p14 and 9p21-p24 and p53 mutation were detected only in the mesenchymal component in the primary tumor but not in the epithelial component in the primary tumor and the brain metastasis. Likewise, AI at chromosome regions 6p24-p25 and 6q14-q27 was detected in the epithelial component in the primary tumor and the brain metastasis but not in the mesenchymal component in the primary tumor. Furthermore, the genetic alterations detected in the metastatic tumor were completely the same as those in the epithelial component in the primary tumor, indicating that a tumor cell(s) in the epithelial component in the primary tumor selectively metastasized to the brain. These results indicate that this biphasic tumor is of monoclonal origin and the phenotypic heterogeneity of the tumor is due to the differences in the accumulated genetic alterations in each component of the tumor.
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PMID:Clonality and heterogeneity of pulmonary blastoma from the viewpoint of genetic alterations: a case report. 1735 Jan 38


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