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)

A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In both instances, the analysis can be performed under a single set of conditions. When testing the assay on DNA from cultured lung cancer cell lines and from paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21 of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A substantial proportion of these significant mutations occurred outside the evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the importance of a comprehensive TP53 mutation analysis in those instances that TP53 mutation is taken into account for diagnostic and prognostic purposes.
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PMID:Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue. 1040 87

Comparative genomic hybridization (CGH) is used to detect amplified and/or deleted chromosomal regions in tumours by mapping their locations on normal metaphase chromosomes. Forty-five sporadic colorectal carcinomas were screened for chromosomal aberrations using direct CGH. The median number of chromosomal aberrations per tumour was 7.0 (range 0-19). Gains of 20q (67%) and losses of 18q (49%) were the most frequent aberrations. Other recurrent gains of 5p, 6p, 7, 8q, 13q, 17q, 19, X and losses of 1p, 3p, 4, 5q. 6q, 8p, 9p, 10, 15q, 17p were found in > 10% of colorectal tumours. High-level gains (ratio > 1.5) were seen only on 8q, 13q, 20 and X, and only in DNA aneuploid tumours. DNA aneuploid tumours had significantly more chromosomal aberrations (median number per tumour of 9.0) compared to diploid tumours (median of 1.0) (P < 0.0001). The median numbers of aberrations seen in DNA hyperdiploid and highly aneuploid tumours were not significantly different (8.5 and 11.0 respectively; P = 0.58). Four tumours had no detectable chromosomal aberrations and these were DNA diploid. A higher percentage of tumours from male patients showed Xq gain and 18q loss compared to tumours from female patients (P = 0.05 and 0.01 respectively). High tumour S phase fractions were associated with gain of 20q13 (P = 0.03), and low tumour apoptotic indices were associated with loss of 4q (P = 0.05). Tumours with TP53 mutations had more aberrations (median of 9.0 per tumour) compared to those without (median of 2.0) (P = 0.002), and gain of 8q23-24 and loss of 18qcen-21 were significantly associated with TP53 mutations (P = 0.04 and 0.02 respectively). Dukes' C/D stage tumours tended to have a higher number of aberrations per tumour (median of 10.0) compared to Dukes' B tumours (median of 3.0) (P = 0.06). The low number of aberrations observed in DNA diploid tumours compared to aneuploid tumours suggests that genomic instability and possible growth advantages in diploid tumours do not result from acquisition of gross chromosomal aberrations but rather from selection for other types of mutations. Our study is consistent with the idea that these two groups of tumours evolve along separate genetic pathways and that gross genomic instability is associated with TP53 gene aberrations.
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PMID:Chromosomal gains and losses in primary colorectal carcinomas detected by CGH and their associations with tumour DNA ploidy, genotypes and phenotypes. 1040 63

The enzyme, thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF), which acts as a potent angiogenic factor. The present study immunohistochemically examined the expression of dThdPase in human colorectal mucosa, adenomas and carcinomas, as well as six cultured colorectal carcinoma cell lines, in terms of intratumoral microvessel density (IMVD) and P53 expression. Thymidine phosphorylase was observed in lymphocytes, fibroblasts and macrophages, as well as smooth muscle cells and Schwann cells in the peripheral nerve fibers. The dThdPase-positive stromal cells apparently outnumbered the normal epithelial cells, adenoma and carcinoma cells with dThdPase. Weak but obvious cytoplasmic immunoreactivity was noted in a few normal colonic epithelia, predominantly the upper surface area, while a few adenoma cells showed weak nuclear immunostaining for dThdPase in six (24%) of the 25 colonic adenomas. Expression of dThdPase was noted in 33 (73.3%) of the 45 Dukes A and B, 14 (51.9%) of the 27 Dukes C and 14 (56.0%) of the 25 Dukes D carcinomas. The mean IMVD was 84.0 +/- 26.2 in the 36 dThdPase-negative carcinomas and 97.9 +/- 31.6 in the 61 dThdPase-positive carcinomas, the value being significantly higher in the latter group (P < 0.05). The frequency of dThdPase expression was significantly lower in the P53-negative carcinomas than in the positive carcinomas (P < 0.05). Western blot analysis showed the highest expression of dThdPase in LoVo carrying the wild-type p53 gene, followed by Colo201, Colo320, DLD-11 and WiDr carrying the mutated gene. These results indicate that: (i) the main source of dThdPase is stromal cells, including lymphocytes and macrophages in both colorectal normal and carcinoma tissues; (ii) dThdPase may take part in the induction of intratumoral microvessels, regardless of tumor stage; and (iii) expression might be modulated by not only P53 but also other molecules.
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PMID:Thymidine phosphorylase expression in human colorectal mucosa, adenoma and carcinoma: role of p53 expression. 1046 91

Overexpression of nuclear p53 and DNA ploidy were analyzed in a series of 65 colorectal adenocarcinomas and correlated with standard clinical and pathological variables (Dukes stage, tumor site, histological grade and type, and nature of the tumor margins). Immunohistochemical tests were done with the DO-7 monoclonal antibody, using formalin-fixed tissue samples and an antigen retrieval solution. Levels of p53 expression were evaluated using a semiquantitative grading system (CAS 200, BD). Nuclear staining of more than 15% of neoplastic cells was observed in 35 samples (53.8%), which were classified as p53-positive. DNA content was measured by flow cytometry in samples of fresh tissue. Tumor site had a significant direct relationship with DNA ploidy (p < 0.01) and p53 expression (p < 0.001). Proximal tumors were more frequently diploid than were distal tumors (78.6% vs 32%). Moreover, distal neoplasms showed more p53 expression than proximal tumors (64.6% vs 14.3%). However, there was no correlation between the other clinical or pathological variables and the pathological parameter p53 expression and DNA ploidy. Our data support the hypothesis that mechanisms of colorectal carcinogenesis may differ in proximal and distal neoplasms.
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PMID:Colon cancer: p53 expression and DNA ploidy. Their relation to proximal or distal tumor site. 1047 66

p21/WAF1 expression was studied in a series of 162 colorectal carcinoma patients and its relation to p53- and activator protein (AP)-2 expressions and to stage as well as survival was assessed. p21 expression was moderate or intense in 33% of the tumours, and 53% of the tumours had moderate or strong p53 staining intensity. Eighty-nine percent of the tumours showed a weak cytoplasmic AP-2 signal. As expected, p21 and p53 stainings were inversely related to each other (P < 0.001). There was a significant positive association between p21 and AP-2 expression levels (P= 0.01). p21 intensity and percentage were higher in Dukes' A and B stages (P< 0.001). The cancer-related survival and recurrence-free survival (RFS) rates were significantly lower among patients with a low signal for p21 (P< 0.001) and low p21 percentage in tumour epithelium (P < 0.001). High p53 staining intensity in tumour epithelium predicted poor survival (P = 0.01) and RFS (P = 0.003). In the multivariate analysis, p21 percentage distribution independently predicted cancer-related survival in all cases, and p21 expression intensity in T1-4/N0-3/M0 and T1-3/N0/M0 cases. p21 percentage distribution was an independent predictor of RFS in all and T1-3/N0/M0 cases. AP-2 staining did not reach any prognostic significance. These results suggest that the immunohistochemical detection of cyclin-dependent kinase inhibitor p21 could be used to predict more precisely the outcome of colorectal cancer patients.
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PMID:p22/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis. 1048 24

Thymidine phosphorylase (dThdPase)/platelet-derived endothelial cell growth factor is expressed at higher levels in a variety of human carcinomas than it is in adjacent normal tissue. The higher expression is associated with an increase of intratumoral microvessel density (IMVD) and an unfavorable patient prognosis. We examined the role of dThdPase in apoptosis, cell proliferation, IMVD, and p53 expression in human colorectal carcinomas. dThdPase expression was noted in 13 of 36 (36.1%) Dukes' A and B carcinomas and in 13 of 28 (46.3%) Dukes' C and D carcinomas. At least 10 areas consisting of carcinoma cells with diffuse dThdPase expression from the 26 dThdPase-positive tumors (category I) and 10 areas without dThdPase expression from the 38 negative tumors (category II) were selected from each case. For stage A and B tumors, the mean IMVDs were 64.8 +/- 33.7 in category I and 33.2 +/- 12.6 in category II tumors, whereas for stage C and D tumors, the mean IMVDs were 77.6 +/- 27.2 in the category I and 34.7 +/- 14.0 in the category II tumors. The mean IMVD was significantly higher in category I than in category II tumors (P < 0.01). The mean apoptotic indices (AIs; percentage of apoptotic cells) were 2.7 +/- 1.7 in the category I and 5.4 +/- 2.2 in the category II carcinomas of stages A and B and 1.4 +/- 0.5 in category I and 5.3 +/- 2.3 in category II carcinomas of stages C and D, and the value of the mean AI was significantly lower in category I than in category II (P < 0.01), regardless of the Dukes' stage. AI and IMVD showed a significant inverse correlation (P < 0.001). There was no significant difference in the frequency of p53 expression between the two categories. These results indicated that dThdPase expression provides an advantage for tumor growth of human colonic carcinomas not only by increasing the intratumoral microvessels but also by attenuation of apoptosis, which might occur via a p53 gene-independent pathway.
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PMID:Thymidine phosphorylase expression is associated with both increase of intratumoral microvessels and decrease of apoptosis in human colorectal carcinomas. 1051 20

About 40% of patients with colorectal carcinoma will develop local or distant tumour recurrences. Integrated analyses of bio-pathological markers, predictive of tumour aggressiveness, may offer a more rational approach to planning adjuvant therapy. To this end, we analysed the correlation between p53 accumulation, Bcl-2 expression, DNA ploidy, cell proliferation and conventional clinico-pathological parameters by testing the prognostic significance of these variables in a series of 171 colorectal carcinoma patients with long-term follow-up. The relationships among the various bio-pathological parameters, analysed by multiple correspondence analysis, showed 2 different clinico-biological profiles. The first, characterised by p53 negativity, Bcl-2 positivity, diploidy, low percentage of cells in S-phase (%S-phase), a low Ki-67 score, is associated with Dukes' A-B stage, well differentiated tumours and lack of relapse. The second, defined by p53 positivity, Bcl-2 negativity, aneuploidy, high %S-phase and elevated Ki-67 score, correlates with Dukes' C-D stage, poorly differentiated tumours and presence of relapse. When these parameters were examined according to Kaplan-Meier's method, significantly shorter disease-free (DFS) and overall survival (OS) were also observed in patients bearing p53 positive and Bcl-2 negative tumours, in Dukes' B stage. In multivariate analysis, p53 accumulation and Bcl-2 expression emerged as independent predictors of a worse and better clinical outcome, respectively. Our results indicate that, in colorectal adenocarcinomas, a biological profile, based on the combined evaluation of p53 and Bcl-2, may be useful for identifying high risk patients to be enrolled in an adjuvant setting, mainly in an early stage of the disease. Int. J. Cancer (Pred. Oncol.) 84:545-552, 1999.
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PMID:Evaluation of multiple bio-pathological factors in colorectal adenocarcinomas: independent prognostic role of p53 and bcl-2. 1056 96

We investigated the prognostic significance of p53 alterations in a consecutive series of 122 Dukes' C rectal carcinomas with a median patient follow-up period of 56 months. One third of patients were treated with post-operative adjuvant chemotherapy. Overexpression of p53 protein was observed in 42% (50/118) of cases using immunohistochemical analysis and mutation of the p53 gene in 38% (47/122) using single strand conformation polymorphism technique. Neither p53 overexpression nor mutation were associated with significantly worse patient survival in the overall group or in the subgroup of 35 patients who received standard post-operative chemotherapy with 5-fluorouracil and levamisole. Our results do not support the use of p53 alteration as a clinically useful prognostic marker for the overall survival of rectal cancer patients or for predicting their response to chemotherapy.
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PMID:P53 alterations have no prognostic or predictive significance in Dukes' C rectal carcinomas. 1056 34

There is no unanimity about the prognostic significance of lymph node micrometastases from colorectal cancer. A case-control study of patients with recurrent and nonrecurrent colorectal cancer who were closely matched for the Dukes stage, extent of lymph node dissection, tumor size, tumor location, number of resected lymph nodes, age and gender was performed. The presence of micrometastases in a total of 1,633 lymph nodes from 44 patients (22 with and 22 without recurrence) were examined by immunohistochemistry using antibodies for cytokeratin (KL-1) and p53 (RSP53). Immunostaining with KL-1 revealed micrometastases in 15/22 patients [68%; 82/820 lymph nodes (10%)] and 15/22 patients [68%; 45/813 lymph nodes (6%)] in the recurrent and nonrecurrent groups, respectively. Immunohistochemical analysis, using RSP53, of 18 paired patients with p53-positive primary tumor revealed micrometastases in 4/9 patients [44%; (7/265 lymph nodes (2.6%)] and 4/9 patients [44%; 6/257 lymph nodes (2.3%)] with and without recurrence, respectively. Neither the micrometastatic frequencies of the patients nor the resected lymph nodes of the recurrent and nonrecurrent groups differed significantly. Micrometastases in regional lymph nodes are an interesting phenomenon, but do not influence patients' prognoses if the involved lymph nodes are removed.
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PMID:Clinical implications of lymph node micrometastases in patients with colorectal cancers. A case control study. 1057 11

To evaluate both the clinicopathological and prognostic significance of p53 protein, the expression of p53 protein was immunohistochemically examined by use of CM1, PAb1801, DO7, and DO1 antibodies on paraffin-embedded colorectal adenocarcinomas from 293 patients. Overexpression of the p53 protein was present in 49% of the samples studied with CM1, 18% with PAb1801, 30% with DO7, and 44% with DO7. The p53 overexpression, as detected by any of the antibodies, tended to associate with distal colorectal, non-mucinous, DNA nondiploid, and higher proliferatively active tumors (P < 0.05) but was irrespective of the patient's gender, age, tumor growth pattern, or Dukes' stage (P > or = 0.05). The p53 protein that was detected by CM1 in either the nucleus (P = 0.007) or the cytoplasm (P = 0.0005) was an independent prognostic indicator. DO1 staining correlated with poor prognosis in the patients with Dukes' B tumor (P = 0.02). However, neither PAb1801 nor DO7 staining could predict prognosis (P > 0.05). p53-positive staining by any of the antibodies predicted significantly poor prognosis compared with p53-negative reactivity (P = 0.007). These results suggest that there was essentially no difference in the significance of p53 overexpression as detected by any of the four antibodies with regard to clinicopathological variables. However, CM1 was the best antibody for predicting prognosis in this series of colorectal cancer patients.
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PMID:Evaluation of four antibodies in detecting p53 protein for predicting clinicopathological and prognostic significance in colorectal adenocarcinoma. 1063 50


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