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)

The liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) is a major liver cancer in Northeast Thailand. The molecular basis of this ICC is poorly understood. To address possible roles of the DNA mismatch repair (MMR) system in ICC carcinogenesis, a fluorescence-labeling PCR/laser scanning technique with high sensitivity was employed to analyze genomic instability in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in 24 fresh and 13 formalin-fixed, paraffin-embedded tissues of ICC and their corresponding normal parts. Microsatellite instability (MSI) was assessed in nDNA, using 12 highly polymorphic loci including 5 Bethesda markers. These loci were mainly related to major MMR genes, hMSH2 and hMLH1. Also 3 (C)n and/or (C)n(A)n repeat instability at 1 noncoding region in the displacement-loop (D-loop) and 2 coding sequences in NADH dehydrogenase subunit 1 and subunit 5 gene in mtDNA were analyzed. MSI was only detected in 1 (2.7%), 6 (16.7%), 1 (2.9%), 1 (2.9%) or 2 (6.3%) out of 37, 36, 35, 35 or 32 cases at BAT-25, D2S123, D3S1611, D11S904 or D17S250, respectively. LOH was found at D3S1298, D3S1561, D5S346 and TP53 in 4 (18.2%) out of 22, 2 (18.2%) out of 11, 6 (33.3%) out of 18 and 3 (12.5%) out of 24 informative cases, respectively. In mtDNA, none except a single case out of the 37 (2.7%) exhibited repeat sequence instability in the D-loop. We conclude that the liver fluke infection-associated ICC in Thailand is classified as low frequency MSI or microsatellite stable type and that DNA MMR system, through hMSH2 and hMLH1 gene mutations, does not play a major role in its carcinogenesis.
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PMID:Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand. 1450 36

The etiology of gastric cancer (GC) is multifactorial, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. This article reviews the considerable progress that has been achieved in understanding the genetics of GC. The genetic effects consist of inherited genetic factors that predispose to GC, and the genetic targets of neoplastic progression that confer altered growth capacity to neoplastic cells. Inherited genotypes include germline mutations of high-penetrance genes directly associated with hereditary GC syndromes and genetic polymorphisms that indirectly affect the susceptibility to GC after exposure to carcinogens or Helicobacter pylori infection. Based on accumulation of different oncogenes or tumor suppressor genes alterations, 2 broad classes of genetic pathways called suppressor and mutator phenotypes are defined that participate in the development and progression of GC. Examples of genes involved in pathogenesis of GC include p53, adenomatous polyposis coli (APC), beta-catenin, E-cadherin, transforming growth factor (TGF)-betaRII, and hMLH1. Delineating genes involved in different subtypes of GC can reflect the heterogeneity and biologic characteristics of GC. Elucidation of the role of inherited genotypes and genetic alterations at different stages of gastrocarcinogenesis may provide a more coherent picture of the mechanism of this devastating disease and facilitate the development of novel approaches to effective prevention and intervention. Advances in high throughput technologies and functional genomics have rapidly increased our understanding of gene structure and function and its role in disease.
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PMID:Genetic alterations and polymorphisms in gastric cancer. 1451 82

Genetic alterations at chromosome arm 8p are associated with advanced disease and poor patient outcome in several types of malignant tumors. We studied the frequency of microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosome 8p in early stage non-small cell lung cancer (NSCLC) of 47 patients with stage I or II disease (25 squamous cell carcinomas and 22 adenocarcinomas). Microsatellite analysis was performed after laser microdissection using 5 polymorphic tetranucleotide microsatellite markers and 4 dinucleotide markers at chromosome 8p. A pentanucleotide repeat marker at the chromosomal locus 17p13.1 (TP53.Alu) was also analyzed. Expression of the mismatch repair (MMR) proteins hMSH2, hMSH6 and hMLH1 was evaluated by immunohistochemistry. Microsatellite instability (MSI) in at least 2 markers was detected in 9 of 47 patients (19.1%) and was predominantly found at tetranucleotide repeats. Sixteen of 47 (34.0%) NSCLC demonstrated LOH at chromosome 8p. All MSI-positive tumors showed normal expression of the MMR proteins. The presence of MSI at chromosome 8p was associated with lymph node metastasis (p=0.02), squamous differentiation (8/25; 32%-p=0.03), and the presence of LOH at the p53 locus (p=0.06). None of the other investigated clinical, pathologic or molecular factors correlated with MSI. Our study showed that an elevated MSI at selected tetranucleotide sequences (EMAST) on chromosome 8p is frequent in early stage squamous cell carcinomas of the lung with lymphatic spread. The tetranucleotide marker panel used in this study was able to indicate lymph node metastasis and high risk disease in patients with resectable squamous cell lung cancer.
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PMID:Microsatellite instability at chromosome 8p in non-small cell lung cancer is associated with lymph node metastasis and squamous differentiation. 1453 77

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.
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PMID:Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma. 1456 78

Gemcitabine [2',2'-difluoro-2'-deoxycytidine (dFdCyd)] is a potent ionizing radiation sensitizer in solid tumor cells in vitro and in vivo. Previously, we have demonstrated (Shewach et al., Cancer Res., 54: 3218-3223, 1994) a strong correlation between depletion of dATP (caused by dFdCyd diphosphate-mediated inhibition of ribonucleotide reductase) and radiosensitization. In addition, we and others (Latz et al., Int. J. Radiat. Oncol. Biol. Phys., 41: 875-882, 1998; Ostruszka and Shewach, Cancer Res., 60: 6080-6088, 2000) have shown that the accumulation of cells in S phase prior to irradiation is also important for radiosensitization with dFdCyd. This led us to hypothesize that the incorporation of incorrect nucleotides because of the dATP pool imbalance was important for radiosensitization with dFdCyd, and, therefore, cells deficient in mismatch repair (MMR) would exhibit greater radiosensitization. We tested this hypothesis by evaluating the ability of HCT116 colon carcinoma cell lines, which differ in MMR proficiency, to be radiosensitized by dFdCyd. The MMR-proficient cell line (HCT116 + ch3) was more sensitive to dFdCyd alone than were the MMR-deficient cell lines (HCT116, HCT116 + ch2, and HCT116 p53(-/-)). Interestingly, the MMR-proficient cells could not be radiosensitized at concentrations of dFdCyd <or=IC(90), although extremely high concentrations of dFdCyd (>IC(96)) enhanced cell killing with radiation. In contrast, the MMR-deficient cells were radiosensitized at concentrations of dFdCyd <or=IC(50), with radiation enhancement ratios of approximately 1.5. Cell cycle analysis, using dual parameter flow cytometry, demonstrated that all of the cell lines accumulated in S phase after dFdCyd treatment, and, shortly after irradiation, a prominent but transient G(2)-M block was observed. In the MMR-deficient cells, the IC(50) for dFdCyd produced a >or=80% decrease in dATP within 4 h after drug addition, and this low dATP level was maintained for another 12-20 h. Although the IC(50) of dFdCyd was unable to sustain a >80% decrease in the dATP level in the MMR-proficient cells, the IC(90) did achieve this level of dATP depletion; however, it was unable to radiosensitize the MMR-proficient cells. Similar results were obtained with HCT116 cells, in which the MMR deficiency was corrected by transfection with a vector containing the hMLH1 cDNA. In addition, the deletion of p53 did not increase radiation enhancement ratios. These results demonstrate that MMR deficiency promotes radiosensitization with dFdCyd. We suggest that dATP depletion produces errors of replication in MMR-deficient cells, which, if left unrepaired, enhances cell death by ionizing radiation.
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PMID:Enhanced radiosensitization with gemcitabine in mismatch repair-deficient HCT116 cells. 1458 94

Cervical cancer is the most common gynecologic malignancy of the developing world. The oncogenic role of human papilloma virus (HPV) is well known. Attention is now focusing on the complicit genetic changes, which allow progression of these tumors. Regarding these changes, deletion of tumor suppressor genes (loss of heterozygosity [LOH]) is the preferred pathway of progression with only a subset manifesting microsatellite instability (MSI). Implicated loci include 3p14.1-22. Several studies suggest that the mutator phenotype in cervical cancer may correlate with higher grade tumors, more advanced disease stage, and poor outcome. Unlike colorectal cancer, in which an inverse relationship has been demonstrated between microsatellite instability and loss of heterozygosity, cervical cancers expressing MSI have been found to coexpress LOH at other loci. In this study we analyzed 8-microsatellite loci including p53, DCC, APC, the MMR gene hMLH1 and 2 regions of interest on chromosome 3 in a high-risk population group in which HPV infection is endemic.
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PMID:Microsatellite analysis of early stage (Ia-IIb) uterine cervical squamous carcinoma. 1461 20

Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.
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PMID:Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. 1463 9

DNA mismatch repair (MMR) plays a key role in the cytotoxic response of human cells to methylating agents, however, the cascade of events leading to cell cycle arrest and cell death has yet to be characterized. We studied the role of MMR in the transcriptional response to DNA methylation damage in two human cellular models: (a). the lymphoblastoid cell line TK6 and its derivative MT1, which is mutated in the MMR gene hMSH6; and (b). the epithelial cell line 293T Lalpha in which the expression of the MMR gene hMLH1 can be tightly regulated and p53 is inactivated. Upon N-methyl-N'-nitro-N-nitrosoguanidine treatment, only cells with functional MMR were killed, but the type of cytotoxic response differed. In TK6 cells, S-phase arrest and apoptosis were accompanied by a dramatic change in gene expression, notably, an up-regulation of several genes encoding growth inhibitors and proapoptotic factors both p53 dependent and independent. In contrast, the MMR-dependent transcriptional response in 293T Lalpha cells was substantially less pronounced than in TK6 cells, despite an efficient induction of a G(2)-M checkpoint and nonapoptotic cell death. Thus, we demonstrate that in human cells of different origin, MMR-mediated killing by methylating agents occurs through different pathways and regardless of the p53 status. Moreover, once DNA methylation damage has been processed by the MMR system, tumor cells might be committed to die, although one or more of their signaling pathways are impaired.
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PMID:Mismatch repair-dependent transcriptome changes in human cells treated with the methylating agent N-methyl-n'-nitro-N-nitrosoguanidine. 1467 70

At least two forms of genomic instability have been described in colorectal cancers (CRCs): microsatellite instability (MIN), which is characterized by a high frequency of microsatellite instability (MSI-H) and chromosomal instability (CIN), which is characterized by losses and gains of chromosomes (aneuploidy), as well as chromosome rearrangements. Morphological and molecular heterogeneity within MIN(-) CRCs have been described, but the distinctions between MIN(-) tumors with CIN and those without CIN remain largely unknown. We studied 179 colorectal cancers to elucidate the clinicopathological characteristics and molecular events in CRCs arising along these pathways. Loss of heterozygosity, MIN, DNA content, mutation of p53 and K-ras, and expression of p53, hMLH1 and hMSH2 were examined. We found that a subtype of tumors (17%) with MIN(-) and CIN(-), differed from MIN(-)CIN(+) tumors with respect to clinicopathological and genetic characteristics. This subtype was associated with a greater frequency of poorly differentiated and/or mucinous tumors (26%). This subtype of tumors had an extremely low p53 gene mutation rate (11%) and a relatively high p53 protein accumulation rate (55%). The dissociation between the p53 gene mutation and protein accumulation suggests that stabilization of p53 protein in the absence of p53 gene mutation may be an important event on a distinct pathway.
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PMID:Colorectal cancer without high microsatellite instability and chromosomal instability--an alternative genetic pathway to human colorectal cancer. 1472 84

Adenocarcinoma of the small intestine (ACSI) is a rare condition with few studies addressing follow-up and prognosis. Tumors of 35 patients with curative resection of an ACSI were retrospectively analyzed by immunohistochemistry: p53, hMLH1, hMSH2 and hMSH6 and microsatellite instability (MSI): BAT-26, BAX, TGF-beta RII. With a median follow up of 6.1 years, the median cancer-specific survival (CSS) was 36.2 months. Patients who were highly instable (MSI-H) (n=10) had a CSS of 49.6 months in contrast to patients with stable tumors (23.2 months) (P=0.010). Additionally, a low tumor stage according to UICC and MSI-H were shown to be independent factors (P=0.005 and P<0.001) for an increased survival in multivariate analysis. Therefore, it is suggested that analysis of the MSI status might prove useful in discerning prognosis within cancers of the same stage.
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PMID:Prognostic significance of microsatellite instability in curatively resected adenocarcinoma of the small intestine. 1473 26


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