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 genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFbetaRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria (n = 10), families in which at least one of the criteria was not satisfied (n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 (n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases.
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PMID:Extensive molecular screening for hereditary non-polyposis colorectal cancer. 1073 61

The purpose of this study was to elucidate microsatellite instability (MSI) and p53 expression for each tumor in cases with sporadic synchronous multiple colorectal cancers. Twenty-nine patients with sporadic synchronous multiple colorectal cancer were examined. There were sixty-five tumors, all of which indicated adenocarcinoma histopathologically. The MSI was assessed using six microsatellite markers (BAT26, BAT40, D2S136, D5S346, D11S922, D17S250). Tumors with two or more positive loci were determined to be MSI-H (high-frequency MSI), tumors with one positive locus were designated as MSI-L (low-frequency MSI) and tumors lacking apparent instability were designated as MSS (microsatellite stable). In addition, overexpression of p53 protein was examined using immunohistochemical (IHC) methods for each tumor. The DO-7 monoclonal antibody was used in the IHC assessments. The following results were obtained: i) there were nine patients who indicated MSI-H at the first tumor (1-H group) and 20 patients who had MSI-L or MSS at the first tumor (1-LS group). ii) The ratio of cases that indicated MSI-H at the second tumor and beyond in the 1-H group was 88.9% (8/9), which was significantly higher than that of the 1-LS group (30.0%, 6/20) (p=0.0021). iii) The frequency of cases with the right-sided colon in the 1-H group (61.9%) was significantly higher than that of the 1-LS group (27.3%) (p=0.0073). In addition, a significant difference was noted in terms of the ratio of cases with poorly differentiated adenocarcinoma or mucinous carcinoma between the two groups [1-H group (19.0%) vs 1-LS group (0%), p=0.0028]. Furthermore, no distinct relationship between MSI status and p53 overexpression was obtained. In conclusion, we think that sporadic synchronous multiple colorectal cancers should be divided into two types; one type that indicates multiple occurrence of MSI-H consecutive tumors and another type that shows multiple occurrence irrespective of MSI.
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PMID:Microsatellite instability of each tumor in sporadic synchronous multiple colorectal cancers. 1118 44

We studied the MSI (microsatellite instability) status and p53 expression in a series of 71 gallbladder cancers (GCs) of different histologic type. All neoplasms were examined combining a microsatellite analysis at mononucleotide locus BAT-26 and an immunohistochemical study for hMSH2, hMLH1, and p53 proteins and markers of gastric and intestinal differentiation. All the 71 GCs were MSS (microsatellite stable). The p53 protein was found in 100% of undifferentiated GCs, 67% of conventional gallbladder adenocarcinomas, 50% of mucinous adenocarcinomas, and 20% GCs with squamous differentiation. All 71 MSS tumors showed presence of immunohistochemical expression of both hMLH1 and hMSH2 gene products. We concluded that microsatellite instability does not play a role in the developing of GC while p53 seems to be the most important alteration found in a large proportion of these cancers, with the only exception of mucinous and squamous gallbladder carcinomas.
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PMID:Microsatellite instability and p53 expression in gallbladder carcinomas. 1276 14

Micro-satellite instability (MSI) is relevant in the management of colorectal cancers (CRC) and relies on analysis of gene mutations, or production of the proteins involved in DNA mismatch repair (e.g. MLH1, MSH2). p53 mutation is also relevant in MSI, but high-level CRC (MSI-H) demonstrate fewer mutations than low-level (MSI-L) or stable (MSS) cancers. Recently, the importance of gene activity (transcription) in MSI has been identified, where rather than being mutated genes have been downregulated. In this study, 67 sporadic CRC and eight samples of normal bowel were analysed for MSI status (by SSCP) and levels of MLH1, MSH2 and p53 gene transcription (by RT-PCR and scanning densitometry). Micro-satellite instability correlated with gender and site, with more MSI-H CRC in females (P<0.02) and in the right colon (P<0.04). In MSI-H, p53 transcription was markedly reduced (P<0.003). Compared to normal bowel, MLH1 transcription was elevated in all cancers (P<0.01), while MSH2 transcription was elevated only in MSI-H (P<0.04). There was a direct correlation between MLH1 and MSH2 transcription (P<0.001). Although fewer mutations are reported in MSI-H than MSI-L/MSS, these results suggest that reduced p53 transcription might account for decreased tumour suppression in MSI-H. The direct correlation between MLH1 and MSH2 transcription suggests that control of these genes might be coordinated.
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PMID:Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability. 1513 86

We compared the frequency of CpG island methylation phenotype (CIMP), inactivation of APC, p53 and DCC genes and K-ras and BRAF mutations in 39 mucinous carcinomas (MC) and 34 non-mucinous carcinomas (NMC) of the colorectum with different microsatellite instability (MSI) status. The higher incidence of MSI (36% vs. 18%) was observed in MC compared with NMC. APC inactivation and K-ras mutations occurred more frequently in NMC (APC, 88%, p<0.001; K-ras, 58%, p=0.01) than in MC (APC, 24%; K-ras, 28%) regardless of MSI status. BRAF mutation occurred at a higher frequency in MC (18%, p=0.01) than in NMC (0%). However, with respect to inactivation of p53 and DCC, MSI status did matter and in both NMC and MC, more frequent inactivation of p53 and DCC was observed in MSS tumors than in MSI tumors. MSS tumors of NMC had a higher frequency of p53 (58% by IHC, p=0.03 and 83% by LOH, p=0.02) and DCC inactivation (83%, p=0.02) compared to MSI tumors of NMC (p53, 33% by IHC and 20% by LOH; DCC, 20%). MSS tumors of MC also showed a higher frequency of p53 and DCC inactivation (p53, 45% by IHC, p=0.02 and 53% by LOH, p=0.005; DCC, 82%, p=0.001) compared to MSI tumors of MC (p53, 0% by IHC and 0% for LOH; DCC, 17%). MC showed a higher frequency of CIMP compared with NMC (41% vs. 11%, p=0.01). These results indicate that mucinous carcinomas of the colorectum exhibit distinct molecular genetic characteristics and may arise from distinct pathogenic pathways.
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PMID:Mucinous carcinomas of the colorectum have distinct molecular genetic characteristics. 1570 32

Colorectal carcinoma is a frequent malignant tumor, characterized by varying clinical course and response to treatment. At the molecular level, colorectal carcinomas are divided into tumors with chromosomal instability (microsatellite-stable, MSS), microsatellite instability (MSI-H) and low microsatellite instability (MSI-L). The method of tissue microarrays allows for combining materials originating from multiple patients into a single slide, what makes possible to simultaneously investigate large material for the presence of numerous, diversified markers. The study material consisted of 208 cases of colorectal carcinoma. Microsatellite instability was evaluated in frozen material employing the PCR reaction with gel and capillary electrophoresis. Following a standard histopathological assessment, tissue microarrays were prepared using a MTA-1 microarrayer (Beecher) and standard immunohistochemical reactions were performed to detect the presence of bcl-2, CDX-2, Ki67, MLH1, MSH2, MSH6, p16, p53 and survivin. Apoptotic cells were detected using the TUNEL method. The correlations between the reactions were investigated and differences in the expression of the investigated proteins noted in carcinomas with various degrees of microsatellite instability. The agglomeration analysis showed differences in patterns of expression between MSS, MSI-L and MSI-H carcinomas. The discriminant function analysis demonstrated that the MSI-H carcinomas were best differentiated by MLH1, survivin and Ki67 expression, while the MSI-L tumors differed from the remaining colorectal carcinomas by their apoptotic index, local tumor stage (pT), the presence of angioinvasion and mucin production.
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PMID:Correlation of microsatellite status, proliferation, apoptotic and selected immunohistochemical markers in colorectal carcinoma studied with tissue microarray. 1701 73

Colon cancers with microsatellite instability (MSI) demonstrate a host immune response characterized by tumor infiltrating lymphocytes (TILs) that may exert effects upon tumor cell apoptosis and cell proliferation. Accordingly, we compared rates of apoptosis and cell proliferation in colon cancers with defective DNA mismatch repair and their association with phenotypic features and clinical outcome. Primary Astler-Coller stage B2 and C colon carcinomas (n = 329) were analyzed for MSI and for hMLH1 and hMSH2 protein expression. Apoptosis (TUNEL assay) and p53 expression were also analyzed by immunohistochemistry, and TILs were quantified by morphology. DNA ploidy and proliferation (PI: S phase + G(2)M) were evaluated using flow cytometry. MSI-H (n = 58) colon cancers showed increased TILs that were significantly associated with increased apoptosis, higher apoptosis to proliferation (AI/PI) ratios, reduced proliferative indices (PI) and diploid DNA content. Increased TILs (p = 0.036) and reduced PI (p = 0.042), but not AI or AI/PI, were associated with improved disease-free survival. Tumors with MSI-H (p = 0.032) or loss of hMLH1 or hMSH2 proteins (p = 0.040), or diploidy (p = 0.0015), had better adjusted overall survival rates. Interestingly, similar rates of cell turnover and overlapping survival rates were found in diploid MSS/MSI-L tumors and in MSI-H cases. In conclusion, higher apoptosis/proliferation ratios and reduced cell proliferation are phenotypic features of MSI-H tumors that are associated with increased TILs, indicating an activated immune response that may contribute to their favorable survival rates.
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PMID:Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. 1718 55

Gastric cancers with and those without high-frequency microsatellite instability (MSI-H) represent distinctive pathways of carcinogenesis. The aim of this study was to clarify if expression of p53 related genes involved in angiogenesis is differentially regulated between these cancers. We systematically analyzed the expression of vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), thrombospondin 1 (THBS1), and brain-specific angiogenesis inhibitor 1 (BAI1), and we correlated the results with microvessel count (MVC), MSI status, p53 mutations, and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in gastric cancers. Expression of VEGFA in carcinoma cells was immunohistochemically seen in 46% of 200 cases. VEGFA positivity was significantly associated with higher MVC, vascular invasion, lymph node and distant metastasis, and advanced tumor stage. FGF2 positivity was significantly associated with poor differentiation, depth of invasion, and higher MVC. VEGFA and FGF2 positivities and MVC were lower in MSI-H cancers than in MSI-L or MSS cancers. VEGFA expression was associated with both p53 mutations and PTGS2 expression. Methylation of the THBS1 gene was detected in 6 of 11 cancer cell lines and in 44% of 200 cases. THBS1 methylation was significantly associated with distal location, vascular invasion, distant metastasis, MSI-H, wild-type p53, and higher MVC. The prognosis was worst in patients with cancers that were VEGFA-positive and THBS1 methylation-positive. Gastric cancers with MSI-H were characterized by lower MVC, low frequency of VEGFA, FGF2, and PTGS2 overexpression, and high frequency of THBS1 methylation. Our results suggest that gastric cancers with and those without MSI-H represent distinctive pathways of carcinogenesis, including aberrant expression of factors regulating angiogenesis. The difference may be associated with less aggressive phenotype of these cancers with MSI-H and affect future molecular targeted therapeutics.
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PMID:Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatellite instability. 1737 40

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

The serrated pathway of colorectal carcinogenesis is heterogeneous with respect to its precursor lesions, molecular alterations and its prognosis. The low-risk-subtype of serrated adenocarcinomas is less frequent (<20% of all serrated adenocarcinomas) and characterized by proximal location, BRAF-mutation, high CpG-island methylation with loss of MLH1-expression and MSI-H phenotype. The assumed precursor lesion of this subtype is the sessile serrated adenoma and the 5-year overall survival is >70%. The high-risk-subtype is more frequent (>80% of all serrated adenocarcinomas) and characterized by distal location, KRAS mutation, MSI-L/MSS phenotype, lower CpG-island methylation, and possible p53 accumulation. The assumed precursor lesion is the traditional serrated adenoma and the prognosis is unfavorable (<30% 5-year overall survival). The analysis of MSI status, KRAS and BRAF mutational status and immunohistochemical analyses of hMLH1 and p53 expression enables the distinction between these two subtypes and is therefore clinically relevant, especially since treatment options for the two subtypes may differ in the future.
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PMID:[Serrated pathway of colorectal carcinogenesis]. 1992 Nov 96


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