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)

Centrosome duplication is controlled in a cell cycle-specific manner and occurs once every cell cycle, thereby ensuring the balanced segregation of chromosomes during the mitotic phase. Numerical or structural abnormalities can arise in the centrosomes of malignant cells. Under defective cell cycle checkpoint systems, cancer cells with abnormal centrosomes can survive and re-enter the cell cycle, promoting unbalanced chromosome segregation and genetic instability. We investigated the centrosome aberrations in 33 patients diagnosed with hepatocellular carcinoma (HCC), using fluorescent pericentrin immunostaining. We also studied the p53 mutation, proliferative activity, and DNA ploidy in these cases. In normal hepatocytes, one centrosome was identified per cell as a round dot, usually in the vicinity of the nuclear membrane. However, in cancer cells from HCC tissue, several patterns of centrosome abnormalities occurred, including supernumerary centrosomes and centrosomes with an abnormal shape and size. Although the frequency of abnormal centrosomes in each tissue was relatively low compared with previous reports in other cancers, nevertheless, centrosome aberration was found in 30 out of 33 HCC tissues. The percentage of tumor cells with abnormal centrosomes was significantly higher in the nondiploid tumors (15.8+/-15.9 per thousand ) than in the diploid tumors (5.4+/-5.1 per thousand ) (P<0.05), and tended to be higher in the tumors with p53 mutation (11.6+/-13.1 per thousand ) than in those with wild-type p53 (5.6+/-6.8 per thousand ). Furthermore, 82% of nondiploid tumors exhibited p53 mutation, whereas only 41% of diploid tumors showed p53 mutation. The percentage of tumor cells with centrosome abnormalities were not related to tumor stage, size or proliferative activity. Therefore, our results indicate that hepatic cancer cells, under centrosome aberration and a defective checkpoint system possibly caused by p53 mutation, have the potential for genetic instability and aggressive behavior. This potential effect occurs irrespective of the tumor size or stage.
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PMID:Centrosome aberration accompanied with p53 mutation can induce genetic instability in hepatocellular carcinoma. 1504 20

We report 62 cases of invasive micropapillary carcinoma of the breast characterized by delicate pseudopapillary structures lacking a fibrovascular core and by tubuloalveolar structures freely floating in clear, empty spaces. All patients but 1 were women (median age, 57 years; range, 25-89 years). Tumor size ranged from 0.7 to 10 cm (median, 2.8 cm); 54 (87%) were grade 3. Psammoma bodies were identified in 29 (47%). Focal to massive lymphatic permeation was present in 39 (63%). Architectural features were retained in the node metastases, dermal lymphatics, and recurrences. Fifty-six patients (90%) had metastatic axillary nodes: 18 tumors were estrogen receptor-positive (32%); 11 were progesterone receptor-positive (20%); HER2/neu was overexpressed in 53 (95%) and p53 in 39 (70%). A peculiar immunoreactivity for MUC1 limited to the cytoplasmic membrane oriented toward the stroma and an absence of immunoreactivity for E-cadherin in the same side of the cytoplasmic membrane indicated inversion of cell polarization and a disturbance in the cell adhesion molecules. Of 41 patients with available follow-up, 29 (71%) had local recurrence (mean, 30 months) and 20 (49%) died of disease. These results underscore the aggressive behavior and poor prognosis of this breast carcinoma variant. Aggressive preoperative neoadjuvant chemotherapy should be considered.
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PMID:Invasive micropapillary carcinoma of the breast: clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior. 1519 58

We report a salivary duct carcinoma (SDC) of parotid gland in a 75-year-old male. Initially, it was studied by fine-needle aspiration, which disclosed features of malignancy consistent with a high-grade carcinoma. Histologically, the tumor showed typical features of SDC, predominantly with a solid and apocrine pattern. The aggressive behavior of this tumor was documented by facial palsy and the presence of 12 regional lymph node metastases. Immunohistochemical study showed positivity for cytokeratins (AE1/AE3), cytokeratin 7, GCDFP-15, C-erbB-2, Mib-1, topoisomerase II alpha, p53, and androgen receptors. Diffuse positivity with chromogranin-A, synaptophysin, and Grimelius stains was also observed, suggesting endocrine features. Phosphotungstic acid hematoxylin, antimitochondrial antigen, progesterone and estrogen receptors, cytokeratin 20, and S-100 stains were negative. To our knowledge, this is the first case reported of SDC exhibiting neuroendocrine differentiation.
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PMID:Salivary duct carcinoma with neuroendocrine features: report of a case with cytological and immunohistochemical study. 1534 92

Expression of survivin, a member of the inhibitor-of-apoptosis (IAP) family, is elevated in fetal tissues and in various human cancers originating in the breast, lung, prostate, colon, pancreas, and stomach. Since overexpression of the survivin gene has been linked to poor patient survival in several cancers, survivin may be an important prognostic marker. Mechanisms up-regulating survivin gene expression in cancer are poorly understood. Recently, wild-type p53 was found to repress expression of the survivin gene by binding to the survivin promoter, thereby inhibiting promoter activity. Further, loss of heterozygosity (LOH) at 17p13 distal to the p53 gene is associated with more aggressive behavior of breast cancers. We therefore tested the hypothesis that not only p53 gene mutation but also LOH at 17p13 can up-regulate survivin expression in breast cancer. Survivin mRNA expression was greater in cancers than in uninvolved tissues (p < 0.0001). Mutations of the p53 gene were detected in 5 of 25 tumors; higher survivin gene expression was evident in these. LOH at the D17S938 locus (17p13.1) was found in 10 of 25 tumors, and most of these also showed increased survivin gene expression. Thus expression of survivin may be regulated not only by p53 but additionally by a putative tumor suppressor gene located at 17p13 distal to the p53 gene.
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PMID:Mutations of the p53 gene and loss of heterozygosity at chromosome 17p13.1 are associated with increased survivin expression in breast cancer. 1537 48

Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) is a rare neoplasm with an aggressive behavior, broad differential diagnosis, and unknown histogenesis. To add to knowledge concerning the possible aid of immunohistochemistry in resolving problems in differential diagnosis and to further explore whether that modality points to any specific histogenesis, we undertook an immunohistochemical study of this neoplasm. Fifteen OSCCHTs (including four of the ''large cell" variant) were stained with a range of antibodies, some of which have not been investigated previously in this neoplasm. Cases were stained with AE1/3, EMA, BerEP4, CK5/6, calretinin, WT1, chromogranin, CD56, synaptophysin, CD99, NB84, desmin, S100, CD10, alpha inhibin, TTFI, and p53. Staining was classified as 0 (negative), 1+ (<5% cells positive), 2+ (5% to 25% cells positive), 3+ (26% to 50% cells positive), or 4+ (>50% cells positive). All cases were positive with p53 (two 1+, five 3+, eight 4+), 14 of 15 cases were positive with WT1 (one 1+, thirteen 4+), 14 of 15 with CD10 (three 1+, four 2+, two 3+, five 4+), 13 of 15 with EMA (three 1+, three 2+, two 3+, five 4+), 11 of 15 with calretinin (nine 1+, one 3+, one 4+), 9 of 15 with AE1/3 (eight 1+, one 2+), 4 of 15 with CD56 (one 1+, two 2+, one 4+), 3 of 15 with BerEP4 (two 2+, one 4+), 2 of 15 with synaptophysin (two 1+), and 1 of 15 with S100 (4+). All cases were negative with CK5/6, chromogranin, CD99, NB84, desmin, alpha inhibin, and TTF1. The only noticeable difference in the immunophenotype between typical OSCCHT and the large cell variant was that there was 4 +EMA positivity in three of four cases of large cell variant compared with two of 11 cases of typical OSCCHT. OSCCHT is characteristically positive with AE1/3, EMA, CD10, calretinin, WT1, and p53. Combined EMA and WT1 positivity, the latter usually intense and diffuse, may be of diagnostic value, inasmuch as only a few of the neoplasms in the differential diagnosis are positive with both antibodies. Negative staining with CD99, desmin, NB84, alpha-inhibin, and TTF1 may aid in the cases in which primitive neuroectodermal tumor, rhabdomyosarcoma, intraabdominal desmoplastic small round cell tumor, neuroblastoma, a sex cord-stromal tumor, and metastatic pulmonary small cell carcinoma are in the differential. Calretinin positivity precludes its use in the differential with granulosa cell tumors. The results of this investigation do not settle the issue of histogenesis, which remains enigmatic. The typical age distribution, follicle formation, and calretinin positivity are consistent with a sex cord origin. On the other hand, WT1 and EMA positivity and negative staining with alpha-inhibin would be unusual in a sex cord-stromal neoplasm and can be used as an argument for a surface epithelial origin. Germ cell and neuroendocrine origins seem highly unlikely.
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PMID:An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. 1538 2

Small cell carcinomas of the uterine cervix are rare tumors with an aggressive behavior. Although these tumors can exhibit neuroendocrine differentiation, the criteria for neuroendocrine differentiation are subjective and not well defined. In this study, the authors tentatively defined small cell neuroendocrine carcinoma (SCNEC) as a tumor composed of small cells with at least two of the following: argyrophilic cytoplasm, chromogranin A immunoreactivity, and synaptophysin immunoreactivity. We found 10 cases fulfilling these requirements. Five of the 10 tumors were composed mainly of small ("oat") cells and 5 of mainly larger "intermediate" cells. The majority of both subtypes showed an insular pattern. Three of the 10 SCNECs were pure, whereas the other seven were mixed with adenocarcinoma and/or squamous cell carcinoma or cervical intraepithelial neoplasia. In addition to the definitional markers noted earlier, the tumors were immunoreactive for serotonin (6 cases), somatostatin, gastrin, glucagon, and pancreatic polypeptide. No tumors were immunoreactive for cytokeratin 20. Human papillomavirus (HPV)-18 was detected in all of the pure tumors and both the SCNEC and adenocarcinomatous components in four of the mixed tumors. No other types of HPV were detected. The tumors showed a relatively low frequency of loss of heterozygosity for representative tumor suppressor gene sites; p53 mutations were found in only one case.
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PMID:Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study. 1538 6

Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes. To determine the role of these genes in MCL, we have examined their gene status and expression and their relationship to INK4a/ARF and p53 gene aberrations in 69 tumors. Increased CDK4 gene copy number was detected in 4 of 19 (21%) highly proliferative blastoid variants and was associated with mRNA and protein overexpression. Three additional cases showed mRNA overexpression with no structural alterations of the gene. MDM2 gene overexpression was detected in three blastoid tumors (16%) with no relationship to gene copy gains. INK4a/ARF and p53 aberrations were observed in 13 and 12 tumors, respectively. Four of the seven lymphomas with CDK4 aberrations had concurrent inactivation of p53 gene, whereas only one case had a concomitant homozygous deletion of INK4a/ARF. No other gene alterations were found in the three cases with MDM2 overexpression. Patients with INK4a/ARF deletions or simultaneous aberrations of p53 and CDK4 had a significantly shorter median survival (17 months) than patients with isolated alterations of p53, MDM2, or CDK4 (32 months) and patients with no alterations in any of these genes (77 months). The prognostic impact of the concomitant oncogenic alterations of the p14ARF/p53 and p16INK4a/CDK4 pathways was independent of the proliferation of the tumors. These findings indicate that CDK4 and MDM2 gene alterations mainly occur in MCL with a wild-type INK4a/ARF locus and may contribute to the higher proliferation and more aggressive behavior of the tumors.
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PMID:CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus. 1578 32

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

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.
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PMID:Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. 1608 54

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


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