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)

Prognostication of head and neck cancer (HNCC) involves molecular identification of residual tumor cells, prediction of recurrence, distant metastases or secondary tumors and prediction of the sensitvity to therapy. Biomarkers of HNCC are mutations of p53, p16 and amplification of Cyclin D and E2F4. One hundred and fifty-two HNCC cases have been evaluated for p53, hMLH1, Cyclin D and p16 gene alterations using PCR-SSCP and Western blot analysis. P53 mutations of HNCC have been found in 37.5% of cases. However, 11% of the cases showed p53 mutations in the normal peritumoral mucosa suggesting "field cancerization" process. Mismatch-repair gene mutations (MMR: hMHL1 and hMSH2) occurred with 17 and 8.6% frequency, respectively, while E2F4 mutations were even more frequent (21.4%) in HNCC. Our data suggest that E2F4 overexpression can be caused by the inactivation of the p16 gene in HNCC, while its mutations are most probably associated to the mutations of the MMR genes. These molecular informations can help to predict the biological potential of HNCC as well as the probability of the development of secondary HNCCs.
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PMID:[Genetic marker analysis in head and neck cancer] 1205 Jul 11

Microsatellite instability (MSI) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear. To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% (31/327) of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmann's gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P <.05). By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P <.001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-beta type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 (24/31) or hMSH2 (4/31) expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P =.046). In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.
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PMID:Distinct clinical features and outcomes of gastric cancers with microsatellite instability. 1206 77

Human cell lines established from biliary tract cancers are rare, and only five have been reported previously. We report the characterisation of six new six biliary tract cancer cell lines (designated SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079 and SNU-1196) established from primary tumour samples of Korean patients. The cell lines were isolated from two extrahepatic bile duct cancers (one adenocarcinoma of common bile duct, one hilar bile duct cancer), two adenocarcinomas of ampulla of Vater, one intrahepatic bile duct cancer (cholangiocarcinoma), and one adenocarcinoma of the gall bladder. The cell phenotypes, including the histopathology of the primary tumours and in vitro growth characteristics, were determined. We also performed molecular characterisation, including DNA fingerprinting analysis and abnormalities of K-ras, p15, p16, p53, hMLH1, hMSH2, DPC4, beta-catenin, E-cadherin, hOGG1, STK11, and TGF-betaRII genes by PCR-SSCP and sequencing analysis. In addition, we compared the genetic alterations in tumour cell lines and their corresponding tumour tissues. All lines grew as adherent cells. Population doubling times varied from 48-72 h. The culture success rate was 20% (six out of 30 attempts). All cell lines showed (i) relatively high viability; (ii) absence of mycoplasma or bacteria contamination; and (iii) genetic heterogeneity by DNA fingerprinting analysis. Among the lines, three lines had p53 mutations; and homozygous deletions in both p16 and p15 genes were found three and three lines, respectively; one line had a heterozygous missense mutation in hMLH1; E-cadherin gene was hypermethylated in two lines. Since the establishment of biliary tract cancer cell lines has been rarely reported in the literature, these newly established and well characterised biliary tract cancer cell lines would be very useful for studying the biology of biliary tract cancers, particularly those related to hypermethylation of E-cadherin gene in biliary tract cancer.
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PMID:Establishment and characterisation of six human biliary tract cancer cell lines. 1210 41

To determine the etiologic factors of human oral cancer, we examined the prevalence of microsatellite instability (MSI), the inactivation of mismatch repair (MMR) genes, p53 mutation, and human papillomavirus (HPV) infection (HPV-16, -18, and -33) in 86 Korean oral cancer specimens, including 76 squamous cell carcinomas and 10 salivary gland tumors. MSI was observed in 3 of the 76 squamous cell carcinomas (4%) and 2 of 10 salivary gland tumors (20%). As MSI is a hallmark of the inactivation of the MMR genes, the genetic status of hMSH2 and hMLH1, and hypermethylation of the hMLH1 promoter region were investigated in oral cancers displaying MSI. Inactivation of the hMLH1 gene by either mutation or hypermethylation was observed 4 of the 5 MSI oral cancers. Mutation of the p53 gene was found in 11 of 76 squamous cell carcinomas (14.5%) but not in the salivary gland tumors. PCR assay revealed the presence of HPV DNA in 11 of the 76 squamous cell carcinomas (14.5%) and 4 of the 10 salivary gland tumors (40%). Type 18 HPV DNA was predominant in 11 of the HPV-infected squamous cell carcinomas (72.7%) and 4 of the HPV-infected salivary gland tumors (50%). Two squamous cell carcinoma tissues were found both to be HPV-infected and to harbor the p53 mutation. Our results suggest: i) that MSI plays a role in the pathogenesis of Korean oral cancers, squamous cell carcinomas (4%) and salivary gland tumors (20%); ii) that genetic alteration or hypermethylation of the hMLH1 gene may be the principal inactivating mechanism in Korean oral cancer with MSI; and iii) that inactivation of the p53 gene by either mutation or HPV infection is frequent in Korean squamous cell carcinomas (26%) and salivary gland tumors (40%).
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PMID:Prevalence of microsatellite instability, inactivation of mismatch repair genes, p53 mutation, and human papillomavirus infection in Korean oral cancer patients. 1211 24

Immunohistochemistry (IHC) is a rapid morphological method that allows the detection of proteins involved in different mechanisms of cancer development. It is therefore a useful tool in the study of cancerogenesis. The best known example is the product of the p53 gene, a tumour suppressor gene which is altered in 50% of all human tumors. In fact, these p53 gene mutations lead to cell protein accumulation whereas the p53 product is not detectable in normal cells. This method also enables the detection of fusion proteins which result from chimeric transcript like WT1 in desmoplastic small round cell tumors, ALK in anaplastic large-cell lymphomas and FLI-1 in Ewing's sarcomas. On the contrary, gene inactivation can induce loss of immunostaining. hMLH1 and hMSH2, which are committed in DNA mismatch repair, can be altered in familial digestive carcinomas, such as hereditary non polyposis colorectal cancer. Thus IHC, which allows us to focus on the altered gene by loss of its product in tumoral cells, represents a good alternative to molecular analysis. IHC is also useful to detect the product of oncogene overexpression such as HER-2 in some breast carcinomas, which allows appropriate therapeutic protocols. Finally, IHC can be used in diagnostic, prognostic and therapeutic ends. Nevertheless, difficulties can be en- countered in the interpretation of the results. Therefore, IHC must be performed in quality control trials.
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PMID:[Immunohistochemistry and genotype analysis of tumors. First part: Which future for the immunochemical diagnosis of cancer?]. 1212 91

We have characterized the role of genetic alterations in the development of liver fluke related cholangiocarcinoma. We analyzed the loss of heterozygosity (LOH) and microsatellite instability (MSI) of hMSH2, hMLH1, and p53 genes in 55 patients with intrahepatic cholangiocarcinoma by using polymerase chain reaction based microsatellite markers D2S119, D3S1611, and TP53, respectively and determined the association between microsatellite alterations and patient survival. A total of 27 (49.1%) out of 55 cases exhibited microsatellite alterations in one locus or more. Of 55 samples, 11 (20%) demonstrated MSI at D2S119 and four (7%) showed MSI at D3S1611. LOH was shown in seven out of 36 (19%) informative cases for D3S1611 and 16 out of 50 (32%) for TP53. Microsatellite alterations at loci studied were significantly associated with poor survival (P=0.0098). This study suggests that genetic alterations of DNA mismatch repair genes and tumor suppressor gene p53 may be involved in cholangiocarcinogenesis and these alterations may be of value as prognostic indicators for liver fluke related cholangiocarcinoma.
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PMID:Microsatellite alterations in liver fluke related cholangiocarcinoma are associated with poor prognosis. 1217 38

Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50-60% mutations in the p53 gene and in 10-15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53(+/+),hMLH1(-)) and 2 derivative cell lines with the genotypes p53(+/+),hMLH1(+) and p53(-/-),hMLH1(-). CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53(+/+),hMLH1(+) cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1(+) cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1(+) and hMLH1(-) cells. By contrast, in the p53(-/-) cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53(+/+) cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53(+/+) cells and a short-term arrest followed by apoptosis in p53(-/-) cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.
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PMID:Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. 1220 84

Base excision repair (BER) is a fundamental cellular process used to reduce the cytotoxicity of alkylating agent chemotherapy. Heretofore, no therapeutic agents have targeted this DNA repair pathway. Methoxyamine (MX), which binds abasic sites, acting as an inhibitor of BER, was evaluated in combination with the methylating agent temozolomide (TMZ). Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well. Nude mice carrying these tumors received TMZ alone or in combination with MX or O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine DNA-alkyltransferase, daily i.p. for 5 consecutive days. At the highest tolerable dose of TMZ (120 mg/kg), a tumor growth delay of approximately 9.3 +/- 1.2 days was noted in SW480. Addition of BG resulted in a tumor growth delay of 25 +/- 2.4 days accompanied by significant weight loss (23%) and severe myelosuppression. In contrast, SW480 tumor-bearing mice treated with MX + TMZ had cessation of tumor growth for 50 +/- 13 days and very slow regrowth, yielding tumor growth delays of >70 +/- 14 days (P < 0.002) without additive systemic toxicity. HCT116 and HCT15 xenografts were completely resistant to treatment with TMZ alone or in combination with BG. However, treatment with MX + TMZ induced significant tumor growth delays (20 +/- 1.4 days in HCT116 and 14 +/- 3.1 days in HCT15 xenografts, P < 0.05). These studies demonstrate that a significant enhancement of the antitumor effect of TMZ by MX was observed in human colon cancer xenografts with mismatch repair proficiency and deficiency. DNA BER may be a useful pharmacological target through which tumor cells can be sensitized to alkylating therapeutic agents.
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PMID:Base excision repair as a therapeutic target in colon cancer. 1223 45

Abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to repression of gene expression and contribute significantly to tumorigenesis. Esophageal squamous cell carcinoma (ESCC) is thought to be developed through a multi-stage process, which involves basal cell hyperplasia (BCH), dysplasia (DYS), carcinoma in situ (CIS) and carcinoma. In the present study, we studied the hypermethylation of 10 selected genes in biopsies from normal individuals and resected tissues from ESCC patients. Tumor and neighboring normal and precancerous tissues including BCH, DYS and CIS were microdissected from the resected tissues by laser capture microdissection. Hypermethylation of CpG islands was examined in these samples for 10 genes: p16(INK4a), p15(INK4b), p14(ARF), human leukocyte antigen (HLA)-A, -B, -C, hMLH1, E-cadherin (E-cad), fragile histidine triad and von Hippel-Lindau (VHL). Methylation of two Alu sequences, which neighbor E-cad and VHL, respectively, was used as control to verify the procedure of DNA extraction and chemical modification. In 48 biopsy samples with BCH or DYS, the most frequent hypermethylated genes were p16(INK4a) (18.8%) and p14(ARF) (14.6%). Seventeen out of these 48 samples (35.4%) contained hypermethylation of at least one gene. In the resected tissues, 52% of the BCH and 81% of the tumors showed hypermethylation of at least one gene. Genes hypermethylated in earlier stage lesions were always found hypermethylated at the later stage lesions in the same patient. All of the genes were methylated at some stages and they were clustered into four groups according to their frequencies. The first group of genes, which consisted of p16(INK4a) and p14(ARF), was most frequently hypermethylated in all stages, and the frequencies increased from normal epithelial (0%) to BCH, to displasia/carcinoma in situ and ESCC. Other genes were hypermethylated less frequently. Our results suggest that hypermethylation of key genes, such as p16(INK4a), p14(ARF) and hMLH1, may be used in combination with other molecular changes, such as p53 mutation, in the development of biomarkers for predicting the risk for ESCC.
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PMID:Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma. 1237 81

We examined biological and clinicopathological significance of individual and combined hMLH1, hMSH2, hMSH3 and hMSH6 expression with immunohistochemistry in 301 unselected colorectal cancers. Weak hMLH1 expression was correlated to microsatellite instability (P=0.04), negative p53 expression (P=0.005) and mucinous carcinomas (P=0.02). Weak hMSH2 expression was related to negative ras (P<0.001) and p53 expression (P=0.005), and better survival (P=0.03). hMSH2, hMSH3 and hMSH6, as well as hMLH1, hMSH2, hMSH3 and hMSH6, were combined into a 'functional' and a 'less-functional' group, respectively. Both 'less-functional' groups were/tended to be associated with microsatellite instability, negative ras and p53 expression, and better survival. In summary, hMLH1 and hMSH2 were more important when investigated individually, and the combined groups were more related to the mutator pathway, suggesting that combined deficiencies of the proteins are more efficiently involved in the mutator pathway. Our result from weak versus strong staining may suggest that the intensity of staining should be considered in future studies on mismatch repair proteins.
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PMID:Combined deficiency of hMLH1, hMSH2, hMSH3 and hMSH6 is an independent prognostic factor in colorectal cancer. 1246 83


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