UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.
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PMID:Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. 1128 47

The incidences of microsatellite instability (MSI) and underlying DNA mismatch repair (MMR) defects in pancreatic carcinogenesis have not been well established. We analyzed 100 sporadic and 3 hereditary pancreatic ductal adenocarcinomas for MSI, and high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L) tumors were further analyzed for frameshift mutations of possible target genes and for promoter methylation and mutation of DNA MMR genes, including hMLH1, hMSH2, hMSH3, and hMSH6 genes. Among the 100 sporadic tumors, 13 (13%) were MSI-H, 13 (13%) were MSI-L, and 74 (74%) were microsatellite stable (MSS) tumors. All of the three hereditary tumors from hereditary nonpolyposis colorectal cancer (HNPCC) patients were MSI-H. MSI-H tumors were significantly associated with poor differentiation and the presence of wild-type K-RAS and p53 genes. Patients with MSI-H tumors had a significantly longer overall survival time than did those with MSI-L or MSS tumors (P = 0.0057). Frameshift mutations of hMSH3, hMLH3, BRCA-2, TGF-beta type II receptor, and BAX genes were detected in MSI-H tumors. Hypermethylation of the hMLH1 promoter was observed in 6 (46%) of the 13 sporadic MSI-H tumors but not in any of the 3 hereditary MSI-H tumors or 13 MSI-L tumors. All of the 3 HNPCC cases had germ-line hMLH1 mutation accompanied by loss of heterogeneity or other mutation in the tumor. Our results suggest that pancreatic carcinomas with MSI-H represent a distinctive oncogenic pathway because they exhibit peculiar clinical, pathological, and molecular characteristics. Our results also suggest the principal involvement of epigenetic or genetic inactivation of the hMLH1 gene in the pathogenesis of pancreatic carcinoma with MSI-H.
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PMID:Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. 1130 99

The most common genetic changes associated with lung cancer involve abnormalities of the genes that regulate the cell cycle. Molecular networking of P53 and P16 tumor suppressor genes and K-RAS oncogene exerts a crucial impact on cell cycle regulation and appears to be of major clinical significance for lung cancer evaluation. The present review article summarizes evaluations of P53, P16 and K-RAS in lung cancer with particular focus on biological and clinical implications, as well as on new molecular approaches to the study of these genes: P53 by yeast functional assay, P16 by methylation specific PCR (MSP) and K-RAS by enriched PCR technique.
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PMID:New molecular approaches to lung cancer: biological and clinical implications of P53, P16 and K-RAS studies. 1137 47

The etiology of small cell lung cancer (SCLC) is strongly tied to cigarette smoking, and now there is considerable information concerning molecular abnormalities involved in the pathogenesis of SCLC. Autocrine growth factors such as neuroendocrine regulatory peptides (eg, bombesin/gastrin-releasing peptide) are prominent in SCLC. Dominant oncogenes of the Myc family are frequently overexpressed in both SCLC and non-small cell lung cancer (NSCLC), while the K-RAS oncogene is never mutated in SCLC but it is in 30% of NSCLCs. The most frequent genetic abnormalities involve tumor suppressor genes (TSGs). The TSG p53 is mutated in more than 90% of SCLCs and more than 50% of NSCLCs; the retinoblastoma TSG is inactivated in over 90% of SCLC but only 15% of NSCLCs, and p16, the other component of the retinoblastoma/p16 pathway, is almost never abnormal in SCLC but is inactivated in more than 50% of NSCLCs. The FHIT TSG is inactivated in 50% to 70% of all lung cancers. Recently, we completed a genome-wide allelotyping study using approximately 400 polymorphic markers distributed at around 10 cM resolution across the human genome comparing SCLCs and NSCLCs, looking for all possible TSG sites by loss of heterozygosity. We found that, on average, 17 loci showed loss of heterozygosity in individual SCLCs and 22 for NSCLC, with an average size of loss of 50 to 60 cM, and an average frequency of microsatellite abnormalities of five per tumor. There were 22 different "hot spots" for loss of heterozygosity, 13 with a preference for SCLC, seven for NSCLC, and two affecting both. This provides clear evidence on a genome-wide scale that SCLC and NSCLC differ significantly in the TSGs that are inactivated during their pathogenesis. Acquired hypermethylation of the promoter region of key genes has become one of the most common mechanisms that tumors use to inactivate the function of tumor suppressor and other genes. We recently completed a study of tumor-acquired promoter hypermethylation for nine genes (p16, DAPK, MGMT, GSTP1, RAR beta, FHIT, ECAD, p14ARF, and TIMP1). We found differences in the frequency of RAR beta methylation (70% for SCLC and 40% for NSCLCs). Finally, we looked at the bronchial epithelium accompanying SCLC and NSCLC for the occurrence of clonal alterations using precise laser capture microdissection with subsequent allelotyping for polymorphic markers. In NSCLC, we frequently find clones of cells with molecular abnormalities in histologically affected epithelium (eg, carcinoma in situ, dysplasia, hyperplasia) and occasionally in normal-appearing epithelium in the cases of current or former smokers. In SCLC these histologic preneoplastic changes were minimal. However, in studies of histologically normal respiratory epithelium, we found a several-fold increased rate of allele loss in SCLC compared with NSCLC patients. Thus, the smoking-damaged histologically normal epithelium associated with SCLC appeared genetically scrambled and has incurred significantly more damage than the epithelium accompanying NSCLCs. We conclude that SCLC and NSCLCs do not differ significantly in the number of genetic alterations that occur. However, SCLCs do differ significantly from NSCLCs in the specific genetic alterations that occur. In addition, smoking-damaged bronchial epithelium accompanying SCLCs appears to have undergone significantly more acquired genetic damage than that accompanying NSCLCs. Future studies need to identify the specific genes involved at these multiple sites and determine if these provide new tools for early molecular detection and monitoring of chemoprevention efforts, and serve as specific targets for developing new therapies. Semin Oncol 28 (suppl 4):3-13.
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PMID:Molecular genetics of small cell lung carcinoma. 1147 91

Epidemiological studies have established associations between various reproductive factors and risk of ovarian cancer; it has also been observed that some of these risk factors are only associated with specific histological subgroups. To investigate the correlation of genetic alterations with these risk factors, we examined a consecutive series of 158 ovarian cancer cases treated at the University of Kentucky (1990-96). Common molecular genetic alterations (LOH on chromosome 17, P53 alterations, K-RAS mutations), histological and clinical characteristics of the disease, demographic patient information and survival were evaluated. These latter data were from the Kentucky Cancer Registry. Univariate analysis showed higher frequencies of chromosome 17 loss and P53 mutations in tumors of advanced stage and grade, and in older and post-menopausal women. Non-mucinous tumors were more likely to be classified as late stage, high-grade cancers, and to have chromosome 17 loss and P53 mutations. Survival analysis indicated that stage was the only independent significant variable. When stage was the outcome variable in multiple logistic regression analysis, histology and chromosome 17 loss were significantly associated with poor survival. This case-case study provides evidence that ovarian cancers of mucinous and non-mucinous histology are significantly different with respect to clinical characteristics, survival and molecular alterations. It also lends support to the hypothesis that ovarian cancer is a heterogeneous disease with distinct etiological factors and clinical outcomes, which may require different approaches to treatment.
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PMID:Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival. 1185 93

Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.
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PMID:Genetic alterations in pancreatic carcinoma. 1260 16

Our understanding of the molecular pathology of pancreatic carcinoma has improved tremendously over the past few years due to the development of sophisticated molecular techniques. This knowledge has led to the postulation of a pancreatic tumor progression model. This article describes the molecular oncogenesis of pancreatic carcinoma and points out potential targets for therapeutic interventions. Pancreatic cancer is characterized by the sequential acquisition of somatic mutations in the proto-oncogene K-RAS and the tumor suppressors INK4a,TP53 and DPC4/SMAD4 and by epigenetic alterations, including the overexpression of the "epidermal growth factor" receptor/ligand system. These genetic changes cause a profound disturbance to cell cycle regulation and continuous growth. Further analysis of the underlying molecular mechanisms will offer new diagnostic and therapeutic options and hopefully improve the outcome of this grim disease in the future.
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PMID:[Pancreatic carcinogenesis. Clinical implications]. 1264 72

To investigate the relationship among 8-OH-dG and the development of human lung cancer and cancer related genes, an 8-OH-dG-specific monoclonal antibody and biotin-streptavidin immuno-staining were used to detect the 8-OH-dG in 150 cases of human lung cancer tissues, 120 adjacent lung tissues without cancer cells, 40 benign lung lesions and 40 normal lung tissues. The expressions of P53, C-MYC, K-RAS, BCL-2 and hTERT(human telomerase reverse transcriptase) were determined by immunohistochemistry and the relationship among the 8-OH-dG and these genes was analyzed. The 8-OH-dG were positive in 139 of 150 (92.7%) lung cancer specimens, and the percentage of adduct labeling cell in lung cancer specimens was (24.00 +/- 25.11)% (mean +/- SE). 21 of 120 (17.5%) adjacent lung tissues were adduct positive, and the percentage of adduct labeling cell was 2.42 +/- 5.98%. 4 of 40 (10.0%) benign lung lesions were adduct positive, and the percentage of adduct labeling cell was 0.80 +/- 1.30%, whereas 2 of 40 (5.0%) normal lung tissues were weak positive with 8-oh-dG, and the percentage of adduct labeling cell in this group was (0.34 +/- 1.01)%. The level of 8-OH-dG in lung cancer tissues was significantly higher than that of adjacent lung tissues, benign lung lesions and normal lungs (P < 0.01). The lung cancer patients were stratified by sex, age, cell types and smoking history, but these characteristics were not correlated with the level of 8-OH-dG. In the investigation of the relationship between the 8-OH-dG and five cancer related genes, higher 8-OH-dG levels were observed in lung cancer patients with over-expression of K-RAS and BCL-2 than those of negative expressed patients (P-value were 0.035 and 0.034 respectively), whereas the expression of P53, C-MYC and hTERT were not correlated with level of 8-OH-dG. 8-OH-dG was an important biomarker that may reflect the oxidative DNA damages of cells, and 8-OH-dG may affect K-RAS and BCL-2 genes in the carcinogenesis of lung cancer.
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PMID:[Study of 8-OH-dG and its correlation with several cancer related gene in lung cancer tissues]. 1453 88

We describe a case of Cronkhite-Canada syndrome associated with sigmoid colon cancer, and provide a literature review. A 77-year-old man was diagnosed with sigmoid colon cancer after presenting with hypoproteinemia, nail atrophy, loss of scalp hair, hyperpigmentation, and gastrointestinal polyposis. The findings were consistent with Cronkhite-Canada syndrome. The colon polyps were histologically serrated adenomas, whose crypts showed a saw-toothed growth pattern with dysplasia, or tubular adenoma. Cronkhite-Canada syndrome associated with colon cancer has been reported in 31 cases. The availability of histologic material permitted reexamination of 25 of these cases. Serrated adenoma of the polypoid lesions was retrospectively found in 10 (40%) of the 25 cases. By comparison, the incidence of serrated adenomas has been estimated to occur in about 1% of all general polyps. Taken together, it is suggested that Cronkhite-Canada syndrome associated with colorectal cancer frequently has polyps containing serrated adenoma lesions. In the case described here, microsatellite instability and overexpression of the p53 protein were found in the cancer lesion and serrated adenoma lesions, and none of the lesions showed a loss of heterozygosity of various genes or K-RAS mutations. Thus, genetic alterations between the serrated adenoma and the colorectal cancer was correlated in this case. These findings suggested the possibility of a serrated adenoma-carcinoma sequence in this case of Cronkhite-Canada syndrome.
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PMID:Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions. 1594 6

Gallbladder cancer (GBC) is the most common biliary tract malignancy. There is a tremendous regional variability in its incidence. Risk factors include genetic susceptibility, gender, presence of gallstones, chronic biliary infections, diet and some anatomical anomalies. Several genetic abnormalities have been described which may be aetiologically important as well as carry prognostic significance. These include mutations in the proteins K-RAS and P53, and altered expression of P-glycoprotein, COX-2 and epidermal growth factor receptor. Most patients present at an advanced stage, overall prognosis is very poor. TNM stage and the extent of surgical resection are the most important prognostic factors. Surgery is the only curative therapy reserved for patients with early-stage disease. The role of adjuvant therapy is not fully defined. Patients with advanced disease are managed with systemic chemotherapy that is primarily palliative. Although 5-fluorouracil alone, or in combination, has been most commonly utilised, there is much greater enthusiasm for the combination of cisplatin and gemcitabine. The availability of better drugs and combinations may affect the use of chemotherapy in neoadjuvant and adjuvant settings. Novel targeted therapies require exploration alone or in combination with chemotherapy.
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PMID:Gallbladder cancer: current status. 1516 72

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