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)

p53 overexpression occurs in more than 50% of colorectal carcinomas, which makes it an interesting target for immunotherapy. HLA class I expression on tumor cells is required for the presentation of p53 peptides and an effective T-cell mediated-immune response to ensue. To analyze to which extent p53 and HLA-I expression in a primary tumor reflects expression in liver metastases, we investigated p53, HLA-A and HLA-B/C expression in 82 colorectal carcinomas and 143 associated liver metastases of 82 patients. We used the monoclonal antibodies DO-7 (p53), HCA2 (HLA-A) and HC-10 (HLA-B/C) on formalin-fixed, paraffin embedded tissue. The percentage of expressing cells was estimated. P53 was overexpressed in 73% of the colorectal carcinomas and 66% of liver metastases. HLA-A was expressed in 98% and 96% and HLA-B/C in 100% and 94% of colorectal cancers and liver metastases respectively. There were no significant differences between the primary tumors and the liver metastases for each marker. The concordance was also very high in those cases in which more than one metastasis was available. Discordant cases consisted of tumors in which expression of p53 or HLA-A was lost in the liver metastases, whereas it was present in only a few tumor cells in the primary tumor. The combined analysis of p53 and HLA-I expression in liver metastases demonstrated that both molecules were expressed in 63% of the cases. P53 and HLA-I were expressed in the majority of primary tumors and their associated liver metastases. This allows to select patients for p53-immunotherapy on the basis of p53 and HLA-I expression in the primary tumor.
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PMID:p53 and HLA class-I expression are not down-regulated in colorectal cancer liver metastases. 1506 6

Rare pancreatic neoplasms have been reported that show both endocrine and exocrine differentiation in the neoplastic components. In addition, pancreatic endocrine tumors may contain small, cytologically bland ductules intimately admixed with the endocrine component. It was recently suggested that these ductules represent an intrinsic part of the tumor, ie, that the ductules are neoplastic, and the term "ductulo-insular tumors of the pancreas" was proposed. In the present study, the nature of the ductular component of 16 cases of ductule-containing pancreatic endocrine tumors was investigated at the molecular level. Molecular genetic changes often present in ductal pancreatic neoplasms were not found by immunohistochemistry for DPC4, p53, and ERBB2 and by sequence analysis of KRAS codon 12. An X-chromosome inactivation clonality assay of one such tumor from a female patient indicated that the neuroendocrine component was monoclonal, contrasting with the ductular component that was polyclonal. The lymph node and liver metastases from three patients only contained the neuroendocrine component, and no ductules were observed. Although certain morphologic features of ductule-containing endocrine tumors are reminiscent of the embryonic development of the human pancreas, none of the tumors expressed PDX-1, a transcription factor essential in pancreatic organ development. Based on our results, it is suggested that the ductular component occasionally found in pancreatic endocrine tumors is the result of entrapment of preexisting nonneoplastic ductules and that the tumors are otherwise not distinctive from conventional pancreatic endocrine tumors. Although the phenomenon is rare, it is important to recognize and to distinguish these tumors from true mixed ductal-endocrine neoplasms, which are generally more clinically aggressive. "Pancreatic endocrine tumors with entrapped ductules" would be the preferred nomenclature since it better reflects the nonneoplastic nature of the ductules.
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PMID:Ductuloinsular tumors of the pancreas: endocrine tumors with entrapped nonneoplastic ductules. 1561 69

Both the mutational status and the specific mutation of TP53 (p53) have been shown to impact both tumor prognosis and response to therapies. Molecular profiling of solid tumors is confounded by infiltrating wild-type cells, since normal DNA can interfere with detection of mutant sequences. Our objective was to identify TP53 mutations in 138 stage I-IV colorectal adenocarcinomas and liver metastases without first enriching for tumor cells by microdissection. To achieve this, we developed a harmonized protocol involving multiplex polymerase chain reaction/ligase detection reaction (PCR/LDR) with Universal DNA microarray analysis and endonuclease V/ligase mutation scanning. Sequences were verified using dideoxy sequencing. The harmonized protocol detected all 66 mutations. Dideoxy sequencing detected 41 out of 66 mutations (62%) using automated reading, and 59 out of 66 mutations (89%) with manual reading. Data analysis comparing colon cancer entries in the TP53 database (http://p53.curie.fr) with the results reported in this study showed that distribution of mutations and the mutational events were comparable.
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PMID:Harmonized microarray/mutation scanning analysis of TP53 mutations in undissected colorectal tumors. 1522 90

APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.
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PMID:Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. 1537 5

To date there is no genetic marker that gives accurate information on the prognostic impact for patients with colorectal cancer. A particular clone, not detected in the tumor, could be responsible for the metastatic process. To overcome this problem, genetic alterations were analyzed in metastatic tissues from 58 patients who developed metastases after curative surgery for colorectal cancer. K-ras, p53 and Smad4 alterations were observed in respectively 38, 60 and 27% of the metastases. These frequencies are similar to the ones reported in primary colorectal tumors. Thus, these genetic alterations cannot be used as prognostic biomarkers in patients with colorectal cancer. The metastases were stratified into 3 groups, according to the metastatic localization. K-ras mutations were detected in respectively 75, 26 and 11% of the distant, peritoneal and liver metastases. Loss of Smad4 expression was observed more frequently in the liver (62%) than in other metastases (13%). These results suggest that the genetic changes of the tumor cells indicate the location of the metastases and thus, the route of metastatic spread.
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PMID:Assessment of K-ras, Smad4 and p53 gene alterations in colorectal metastases and their role in the metastatic process. 1554 41

According to recent reports, some cancer types exhibit nonrandom allele loss at codon 72 in exon 4 of the p53 gene [coding for proline (72Pro) or arginine (72Arg)]. To clarify this phenomenon for colorectal cancer and to find out if this preferential loss might have any functional significance, p53 loss of heterozygosity (LOH) and p53 mutations were investigated in a group of 61 colorectal cancers and 28 liver metastases, and were correlated with clinicopathologic factors. A comparison of a patient's blood codon 72 status with a healthy control group did not reveal an enhanced risk of developing colorectal tumors for one of the two isoforms. p53-LOH and p53 mutations were found in 62.2% and 39.4% of primary tumors, respectively, and in 57.9% and 25% of hepatic metastases, respectively. In 14 heterozygous cases showing exon 4-LOH, only the 72Pro allele was lost and the retained 72Arg was preferentially mutated. In general, p53 mutations were significantly associated with the 72Arg tumor status (P < .001). Distal tumors showed allelic losses of the p53 gene more commonly than proximal tumors (P = .054). The prevalence of 72Arg increased in frequency with higher Dukes stage (P = .056). We suggest that either the preferential loss of 72Pro or the mutation of the 72Arg in colorectal cancer and hepatic metastases is associated with malignant potential and might reflect carcinogenic exposure, particularly in the distal part of the large intestines.
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PMID:Selective loss of codon 72 proline p53 and frequent mutational inactivation of the retained arginine allele in colorectal cancer. 1554 61

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.
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PMID:Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. 1564 67

Pleomorphic leiomyosarcoma (PLMS) of the adrenal gland is a rare tumor in an unusual location. A primary PLMS of the left adrenal gland is reported in a 59-yr-old Mexican woman who presented progressive flank pain and weight loss. The tumor measured 16 cm in diameter, showed markedly pleomorphic and osteoclast-like giant cells, necrosis, and high mitotic activity (average 15 per 10 high-power fields). The phenotype was supported by light microscopy and corroborated by immunohistochemistry. The neoplastic cells were strongly positive for muscle-specific actin, desmin, vimentin, and p53. They were negative for CD34, HMB45, estrogen receptors, and S-100 protein. The percentage of Ki-67 positive neoplastic cells was 7.6%. DNA content analysis by flow cytometry showed that tumor was diploid, with a high level of apoptosis. Extra-adrenal primary sites of origin were clinically excluded. The patient developed local recurrence and liver metastases 12 mo after initial treatment. She then received adjuvant chemotherapy and radiotherapy and the metastasis was resected. Twenty-four months later, she is alive with no evidence of disease. This is the second case of adrenal PLMS reported. This case exhibited a high histologic grade, aggressive behavior, and p53 overexpression, but diploid DNA content.
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PMID:Pleomorphic leiomyosarcoma of the adrenal gland with osteoclast-like giant cells. 1600 Aug 50

Most pancreatic endocrine neoplasms (PENs) have distinctive endocrine growth patterns and uniform nuclear morphology; they are regarded as relatively low-grade tumors. Significant nuclear pleomorphism is a feature that may raise concerns about aggressive behavior or even obscure the endocrine nature of the neoplasm. Eight PENs exhibiting marked nuclear pleomorphism (>20% of the tumor cells) were identified during a review of 136 PENs (5.9%) from the pathology files of Memorial Sloan-Kettering Cancer Center. The histologic, immunohistochemical, ultrastructural (4 cases), and clinical features were reviewed. There were 6 males and 2 females ranging from 30 to 69 years (mean, 55 years). The tumors averaged 5.8 cm (range, 1.5-14 cm). Six tumors (75%) were initially misdiagnosed in 5 cases as adenocarcinoma and in one as solid-pseudopapillary tumor; in 2 cases, the misdiagnosis was based on fine needle aspiration cytology and in 4 on histologic examination. The architectural features of the tumors resembled those of other PENs, but the nuclei were markedly enlarged, irregularly shaped, and hyperchromatic, with frequent bizarre forms. Cells with pleomorphic nuclei also generally had abundant cytoplasm, sometimes with large perinuclear glassy inclusions. The mitotic rate was not elevated compared with other PENs, averaging 1.9 (range, 0-7) per 50 high power fields. Immunohistochemical findings were (number positive/number stained): chromogranin (8 of 8), synaptophysin (7 of 8), progesterone receptor (4 of 7), CD99 (2 of 5), S-100 protein (3 of 7), and p53 (0 of 6). Scattered cells expressed peptide hormones in a minority of cases. By electron microscopy, abundant dense core granules were identified, in some cases embedded within perinuclear arrays of intermediate filaments. Six patients underwent curative resection; at follow-up, 4 were free of disease at 11, 13, 30, 112 months (mean, 42 months), 1 developed liver metastases at 77 months and was alive with disease at 94 months, and 1 was lost to follow-up. Two patients had unresectable tumors and were alive with disease at 10 and 78 months. Striking nuclear pleomorphism may occur in otherwise typical PENs and commonly causes difficulties in the distinction from adenocarcinoma. There does not appear to be prognostic significance to these nuclear changes, and the morphologic features of pleomorphic PENs otherwise resemble those of their conventional counterparts.
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PMID:Pleomorphic pancreatic endocrine neoplasms: a variant commonly confused with adenocarcinoma. 1609 9

About 40% of patients bearing a colorectal carcinoma will develop local or distant tumor recurrences. Integrated analyses of biopathological markers, predictive of tumor aggressiveness, may offer a more rational approach to adjuvant therapy planning. To this end we analyzed the correlation between p53 accumulation, bcl-2 expression with cell proliferation, DNA ploidy, and conventional histological parameters, by testing the prognostic significance of these variables in a series of 214 patients bearing a colorectal carcinoma. When these parameters were examined in the univariate analysis, significantly shorter disease free and overall survival were observed in patients bearing p53+ and bcl-2- tumors. In the multivariate analysis p53 accumulation and bcl-2 expression emerged as independent predictors respectively of worse and better clinical outcome also in Dukes' B stage identifying patients at higher risk to develop liver metastases.. These results indicate that in colorectal adenocarcinomas a biological profile, based on the combined evaluation of p53 and bcl-2, can be useful in identifying high risk patients to be enrolled in an adjuvant setting mainly in early stage of the disease.
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PMID:Bio-pathological factors of prognostic value in colorectal adenocarcinomas. 1676 24


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