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 methylation status of seven cancer-related genes was investigated in a series of 58 colorectal cancers, 18 of which showed the microsatellite instability (MSI+) phenotype. Methylation of the hMLH1, p16 and MDR1 genes was found in 23, 29 and 28% of tumors, respectively. None of the tumors showed methylation of the TS, ATM, PARP or p21 genes. Methylation of the hMLH1, p16 and MDR1 genes was more frequent and more concordant in MSI+ compared to MSI- tumors (P<0.001) and was also strongly associated with poor histological differentiation (P<0.001). There were trends for associations between methylation at one or more of these loci and proximal tumor location, advanced Dukes' stage and the presence of wild-type p53 (P=0.06 for each).
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PMID:Methylation of the hMLH1, p16, and MDR1 genes in colorectal carcinoma: associations with clinicopathological features. 1132 3

p27 is a cyclin-dependent kinase inhibitor which regulates progression of cells from G1 into S phase in a cell cycle. Loss of the negative regulator may contribute to oncogenesis and tumor progression. The aim of this study was to examine p27 expression in normal mucosa, primary and metastatic tumors from patients with colorectal adenocarcinomas and to analyze association of p27 with patient survival and clinicopathological variables. p27 expression was estimated by immunohistochemistry in 178 primary colorectal cancers, 34 lymph node metastases and 48 normal mucosa samples from patients with colorectal adenocarcinoma. Associations of p27 with patient survival, clinicopathological characteristics and expression of p53, p73 and DCC were analyzed. Loss of p27 was found in 51% of primary tumors, 68% of metastases and 56% of normal samples. The intensity of p27 staining was similar in the matched primary tumor, metastasis and normal mucosa. In patients with Dukes' B or with proximal tumors, the loss of p27 predicted poorer prognosis (p = 0.03 and p = 0.05, respectively). However, there were no significant differences in the patients with other individual Dukes' stage or distal tumors. No relationships were found between p27 and patients' gender, age, tumor location, growth pattern and expression of p53, p73 and DCC (p > 0.05). The data suggest that loss of p27 was associated with poor prognosis in patients with Dukes' B tumor or those with proximal tumor. p27 might be a useful marker to identify the more progressive tumors in these groups.
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PMID:Loss of p27 expression predicts poor prognosis in patients with Dukes' B stage or proximal colorectal cancer. 1140 21

The quantitative assessment of apoptotic index (AI) and mitotic index (MI) and the immunoreactivity of p53, bcl-2, p21, and mdm2 were examined in tumour and adjacent normal tissue samples from 30 patients with colonic and 22 with rectal adenocarcinoma. Individual features and combined profiles were correlated with clinicopathological parameters and patient survival data to assess their prognostic value. Increased AI was significantly associated with increased bcl-2 expression (p<0.008) and the immunoprofiles that included bcl-2, but not with MI, p53, p21 or mdm2. AI was significantly associated with increased Dukes' stage from A, B to C (p<0.02) but not D, while MI showed a significant association with all Dukes' stages (p<0.05). No significant association was found between either AI or MI and prognosis. p53, p21, mdm2, and bcl-2 positivity were detected in 65.4%, 53.8%, 65.4%, and 34.6% of cases, respectively. mdm2 was significantly associated with p53 (p<0.03) and p21 (p<0.04) expression and p53 immunoreactivity was more prevalent in rectal tumours (p<0.008). In univariate survival analysis, bcl-2 overexpression was associated with more favourable patient survival (p<0.03). Positive combined patterns p53+/p21+/bcl-2+ and p21+/mdm2+/bcl-2+ (p<0.005); p53+/bcl-2+, p21+/bcl-2+, and mdm2+/bcl-2+ (p<0.01); and p53+/p21+ (p<0.02) were also associated with favourable clinical outcome. In multivariate Cox survival analysis, bcl-2 (p<0.016) and Dukes' stage (p<0.0001) were the only significant independent prognostic indicators. In conclusion, bcl-2 immunoreactivity was associated with apoptosis and could be used in combination with Dukes' stage as a means of predicting prognosis in colorectal cancer.
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PMID:Apoptosis and cell-cycle regulatory proteins in colorectal carcinoma: relationship to tumour stage and patient survival. 1152 51

To identify the prognostically highest risk patients, DNA content and p53 nuclear or cytoplasmic accumulation, evaluated by monoclonal antibody DO7 and polyclonal antibody CM1, were determined in 94 surgically resected stage II (Dukes B2) colorectal cancers, treated or not with adjuvant 5-fluorouracil-based chemotherapy. Sixty-one (65%) of the tumors were aneuploid, 16 (17%) of which had a multiploid DNA content; 50 (53%) displayed DO7 nuclear p53 accumulation, and 44 (47%) showed cytoplasmic CM1 positivity. In multivariate analysis, only multiploidy and p53 nuclear positivity emerged as independent prognostic indicators of a poorer outcome. Positivity for p53 was associated with shorter survival in 5-fluorouracil-treated and untreated patients. Therefore, in patients with Dukes B2 colorectal cancer, a biologic profile based on the combined evaluation of DNA multiploidy and p53 status can provide valuable prognostic information, identifying patients to be enrolled in alternative, more aggressive therapeutic trials.
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PMID:p53 nuclear accumulation and multiploidy are adverse prognostic factors in surgically resected stage II colorectal cancers independent of fluorouracil-based adjuvant therapy. 1155 64

Ki-ras mutations are associated with an increased risk of relapse and death in colorectal cancer (CRC) patients, with some mutations being more aggressive than others. The present study examined the predictive value of different Ki-ras mutation types in a retrospective series of 430 Dukes' C stage CRC patients, of whom 208 (48%) had received adjuvant chemotherapy with 5-fluorouracil/levamisole or 5-fluorouracil/leucovorin. A total of 140 mutations were detected, the majority (58%, 81/140) being glycine to aspartate mutations in codons 12 and 13. Glycine to valine mutations in codon 12 (14%, 20/140) and other less frequent, non-specified mutation types (28%, 39/140) accounted for the remaining mutations. Kaplan-Meier survival analysis revealed that both Ki-ras wild-type and mutant patient groups derived significant survival benefit from chemotherapy. However, when patients were stratified according to the type of mutation, those with non-aspartate mutations appeared to gain more benefit from this treatment than those with aspartate mutations. Multivariate analysis that included other possible predictive factors in Dukes' C CRC (tumour site, patient sex, TP53 mutation) demonstrated that non-aspartate mutations in particular were associated with a significant survival benefit from chemotherapy (HR=0.11, 95% CI: 0.04-0.30, p<0.001). These results suggest that the type of Ki-ras mutation could be a clinically useful molecular marker for the identification of CRC subgroups that are likely to benefit from 5-fluorouracil-based adjuvant chemotherapy.
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PMID:Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer. 1174 89

Blood samples were obtained preoperatively from 151 consecutive patients who were operated for colorectal carcinoma; of these 132 patients underwent curatively aimed operations. Patients who lived for more than five years without any evidence of relapse were classified as survivors and those who died during follow-up were classified as non-survivors. Tumors were staged according to Dukes and tumor differentiation was classified as high, intermediate or low. Serum anti-p53 was determined in all patients and compared to CEA, CA 50 and CA 242 in serum as well as to blood hemoglobin concentration (Hb), erythrocyte sedimentation rate (ESR), serum alkaline phosphatases (ALP), in the same preoperative blood samples for comparison of power to predict mortality in colorectal cancer. Tumor differentiation and Dukes classification predicted survival and the risk to die of colorectal carcinoma as expected. CA 242 and anti-p53 titers in serum were not significantly different among groups of patients with Dukes A-D tumors, while Hb, ESR, ALP, CEA and CA 50 were significantly different with increasing levels appearing in Dukes C-D, except for Hb which decreased. Survivors had lower ESR, ALP, CEA, CA 50 and CA 242, while Hb and serum anti-p53 titers were not different among survivors and non-survivors. Survivors among Dukes A-C patients had normal Hb, ESR, ALP and CA 242 before operation, while non-survivors had increased ESR, CEA and CA 50. Levels of anti-p53 were unrelated to concentrations of all other blood and serum variables, and did not predict survival in Dukes A-D patients. Serum levels of CEA and CA 50 displayed a significantly altered distribution among survivors and non-survivors (p<0.01). This altered distribution was independent of Dukes A-C tumor stage for CEA (p<0.05) but not for CA 50. Based on these results, we conclude that patients with CEA levels above 15 ng/ml should be regarded as high risk patients even when their tumors are classified as Dukes B. These patients may benefit from neoadjuvant or adjuvant chemotherapy.
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PMID:Prediction of postoperative survival by preoperative serum concentrations of anti-p53 compared to CEA, CA 50, CA 242 and conventional blood tests in patients with colorectal carcinoma. 1195 98

To clarify the significance of p53 mutations in liver metastasis of colorectal carcinogenesis, the characteristics of p53 mutations from 51 liver metastases and 76 primary invasive carcinomas without liver metastasis (Dukes' A, B and C) were compared. The frequency of tumors with p53 mutations was 61% (31 out of 51) in the liver metastases, and 51% (39 out of 76) in the primary carcinomas without liver metastasis. Approximately 90% of the informative cases having p53 mutation showed 17pLOH. Mutations detected within exons 4-10 of the p53 gene included missense, nonsense, frameshift, inframe deletion, and inframe insertion mutations. Out of the tumors with p53 mutations, we found that the percentage of tumors with protein-truncating mutations (nonsense and frameshift mutations) was extremely higher in liver metastases (16 out of 31, 52%) than in primary carcinomas without liver metastasis (5 out of 39, 13%) (P=0.0005). The present results suggest that protein-truncating mutations of the p53 gene are more relevant than missense mutations as one of the prognostic factors in liver metastasis of colorectal carcinomas.
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PMID:High incidence of protein-truncating mutations of the p53 gene in liver metastases of colorectal carcinomas. 1224 68

NF-kappaB is a transcription factor believed to mediate a cellular survival response following the apoptotic stimulus TNF-alpha. To clarify the role of NF-kappaB in colorectal cancer, we investigated the relationship of NF-kappaB expression by immunohistochemistry with clinicopathological variables, and other factors including apoptotic index, bcl-2 expression, p53 and K-ras mutations in 138 colorectal adenocarcinomas. Eighty-seven (63%) tumours showed cytoplasmic and 51 (37%) nuclear NF-kappaB expression. Nuclear NF-kappaB was correlated with mucinous carcinomas (p=0.006) and was more apparent in the invasive margin of some tumours. A trend was seen between nuclear NF-kappaB expression and K-ras mutation (p=0.15). However, NF-kappaB was not correlated with gender, age, tumour location, Dukes' stage, survival, apoptotic index, bcl-2 expression and p53 mutations. Conclusively, NF-kappaB might be activated in more aggressive colorectal tumour cells, since both tumour cells in the invasive margin and the mucinous tumour cells could represent more aggressive tumour cells.
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PMID:Protein expression of NF-kappaB in human colorectal adenocarcinoma. 1237 89

DNA damage induces p53-mediated cell cycle arrest in which p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, may play a critical role by being regulated via wild-type p53. Although adjuvant preoperative radiotherapy in rectal carcinoma is generally believed to improve the prognosis, it remains unclear which factors control the response. We investigated the interactions between the underlying mechanisms of cell cycle perturbation in response to radiotherapy, and local recurrence and distant metastasis in patients undergoing radical surgery for rectal carcinoma. A retrospective review was carried out in which 63 cases of Dukes' B or C, well or moderately differentiated rectal carcinomas in the lower two-thirds of the rectum, with or without preoperative radiotherapy, were immunohistochemically analyzed using antibodies to p53 and p21WAF1/CIP1. Induced p53 expression in adjacent normal mucosa, as seen in seven of 35 cases with radiotherapy, and mutually exclusive p21WAF1/CIP1 immunoreactivity, was strongly associated with local recurrence (P=0.0001). Furthermore, high p21WAF1/CIP1 expression was associated with a lack of distant metastasis (P=0.032). Our data suggest that there are some cases in which p53 overexpression in adjacent normal mucosa induced by radiotherapeutic treatment might heighten the risk of local recurrence, and that p21WAF1/CIP1 induction independent of the status of the p53 gene showing radiosensitivity might lead to a less distant metastasis.
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PMID:Prognostic values of radiation-induced p53 in adjacent normal mucosa and p21WAF1/CIP1 expression in rectal cancer patients. 1242 71

p53 gene alterations are among the most common events observed in colorectal cancer,and are accompanied frequently by DNA aneuploidy and high proliferative activity. The prognostic significance of such mutations remains controversial. We prospectively evaluated the prognostic significance of p53 mutations, DNA-ploidy, and S phase fraction (SPF) in a consecutive series of 160 colorectal cancer patients (median follow-up 71 months). Tumor DNA was screened for p53 mutations by PCR/single-strand conformational polymorphism/sequencing. DNA-ploidy and SPF were assessed by DNA flow cytometry. p53 mutations were detected in 68 of 160 (42.5%) cases. In 56% (38 of 68) of these, p53 mutations were found in conserved areas of the gene and in 44% (30 of 68 cases) outside the conserved regions. Eighteen of the 68 cases (26%) had mutations in the L3 loop, 11 of 68 (16%) in the L1 loop-sheet-alpha helix motif, and 39 of 68 (58%) outside L3 and loop-sheet-alpha helix. Seventy-five percent of the cases (120 of 160) showed DNA aneuploidy, whereas 18% of these (22 of 120) were multiclonal. The major independent predictors for both disease relapse and death were advanced Dukes' stage, p53 mutations affecting L3 loop, DNA-aneuploid tumors, and high SPF (>18.5%). Our results show that mutations in L3 functional domain, more than any mutations, are important biological indicators to predict the outcome of patients indicating that these mutations have biological relevance in terms of colorectal cancer disease course.
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PMID:p53 mutations in L3-loop zinc-binding domain, DNA-ploidy, and S phase fraction are independent prognostic indicators in colorectal cancer: a prospective study with a five-year follow-up. 1243 9


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