Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007112 (prostatic adenocarcinoma)
 2,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic alterations of multiple loci that serve as markers for the induction and progression of disease have been identified in several adenocarcinomas, but not in adenocarcinoma of the prostate. To determine if similar genetic alterations occur in prostate carcinoma and could serve as markers for the extent of clinical disease, we have examined 23 predominantly moderately-differentiated, localized prostate carcinomas and one prostatic dysplasia for changes in the structure and copy number of ten selected genes. These genes include 1) those important to androgen metabolism in the prostate, the androgen receptor and steroid 5 alpha reductase genes; 2) those that map to the 10q (PLAU) and 7q (MET) chromosomal regions found deleted in some prostate carcinomas, and 3) proto-oncogenes (ERBB2, INT2, and MYC) and tumor suppressor gene loci (RB1, TP53 and D17S5) found altered in adenocarcinomas of the breast, colon and lung. Gene alterations were detected in one specimen, a lymph node metastasis from a poorly differentiated tumor. This specimen exhibited loss of heterozygosity for two loci putatively active in tumor suppression, TP53 and D17S5, on the short arm of chromosome 17. This study indicates that gross genetic alterations were not evident and could not be used as markers of tumor development in well- or moderately-differentiated, localized lesions, but that loss of the 17p region may be a useful marker for advanced carcinomas in the prostate.
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PMID:Loss of the 17p chromosomal region in a metastatic carcinoma of the prostate. 155 12

To determine whether p53 immunoreactivity correlates with the Gleason tumor grade in primary adenocarcinoma of the prostate we analyzed 107 consecutive surgical specimens (78 radical prostatectomies and 29 transurethral resections). A hematoxylin-eosin-stained slide from a representative block of each tumor was examined, and primary and secondary Gleason scores were assigned in each case. Additional paraffin sections from the same block were stained immunohistochemically for p53 expression using the monoclonal antibody clone DO-1, a mouse IgG2a directed against a denaturation-resistant epitope of p53. Four of 54 (7.4%) low-grade tumors (combined Gleason score of 6 and below) and 11 of 53 (20.8%) high-grade tumors (combined Gleason score of 7 and above) revealed strong nuclear positivity for p53. When evaluated using only the primary Gleason score, none of 23 (0%) Gleason grade 2 tumors and 15 of 84 (17.9%) Gleason grade 3 or higher tumors were positive. These data demonstrate a positive association between p53 immunoreactivity and higher Gleason grade tumors (P = .04 for the combined score, P = .02 for primary score only). In addition, we noted occasional p53-positive nuclei in basal cells of benign glandular acini in regions flanking tumor. Focally positive nuclear staining also was demonstrated in basal cells from nine of 25 prostate glands exhibiting benign prostatic hyperplasia with no tumor. These results suggest that p53 overexpression might be associated with the known proliferative capacity of basal cells in benign hyperplastic prostate glands, and that mutations of p53 might play a role in the pathogenesis of a subset of high-grade prostate adenocarcinomas.
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PMID:Association of p53 immunoreactivity with high gleason tumor grade in prostatic adenocarcinoma. 750 86

The multifocal origin of prostate cancer suggests a pan-organ defect in a tumor suppressor pathway. Although structural mutations in the p53 gene have been implicated in late-stage prostate cancer, little is known about the p53 response to genotoxic stress in normal human prostatic epithelial cells from which adenocarcinomas originate. We found that the majority (10 of 12) of epithelial cell cultures derived from histologically normal tissues of radical prostatectomy specimens failed to exhibit p53 accumulation in response to ionizing radiation. Epithelial cell cultures derived from benign prostatic hyperplasia and a primary prostatic adenocarcinoma also failed to accumulate p53 in response to ionizing radiation. In contrast, cultures of prostatic stromal cells derived from normal, benign prostatic hyperplasia, or adenocarcinoma tissues exhibited a 3-9-fold induction of p53 within 1-3 h after irradiation. Since p53 regulates a cell cycle checkpoint through the induction of the cyclin-cdk inhibitor p21, we examined p21 accumulation and cell cycle arrest following exposure to ionizing radiation. With one exception, epithelial cells that did not display increased p53 or p21 induction did not demonstrate a significant G1-S arrest in response to ionizing radiation, whereas stromal cells that accumulated p53 and p21 exhibited a large cell cycle arrest. These results indicate a functional difference between the DNA damage response of epithelial and stromal prostatic cells and suggest a possible mechanism for the increased susceptibility of prostatic epithelial cells to accumulate genetic alterations.
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PMID:Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents. 754 16

Prostate cancer is one of the most common malignancies in men. Few authors have attempted to identify consistent genetic alterations at the molecular level in adenocarcinoma of the prostate, but those most frequently reported are loss of heterozygosity (LOH) involving chromosome arms 8p, 10q, 16q, and 18q and inactivation of the TP53 tumor suppressor gene. In order to determine if alterations frequently found in other adenocarcinomas (breast, ovarian, colorectal), including losses of genetic material from chromosome arms 1p, 3p, 7q, 8p, 11p, 17p, 17q, and 18q, are also involved in prostate cancer, we examined 20 localized early-stage prostate tumors. We detected no mutations of the TP53 gene. Allelic losses were found from 7q (33%), 8p (50%), 10q (20%), and 18q (33%). Furthermore, as the first step toward isolating tumor suppressor genes on 18q, we used six polymorphic markers and identified a small common deleted region between the chromosome 18 centromere and the D18S19 locus.
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PMID:[Genetic alterations in localized cancers of the prostate: identification of a common region of deletion on the chromosome 18q]. 754 22

p53 is a tumor suppressor protein that is overexpressed in a variety of human neoplasms, including prostatic adenocarcinoma. Recent studies have demonstrated a significant positive correlation between extent of p53 overexpression and tumor grade in prostatic adenocarcinoma. Because it appears that mutations of p53 might play a role in the pathogenesis of a subset of biologically aggressive prostatic neoplasms, we sought to examine the frequency of p53 overexpression in primary and metastatic prostatic adenocarcinoma. Using a monoclonal antibody (D07) directed against both the wild-type and mutant forms of p53, we examined p53 immunoreactivity in 36 cases of primary prostatic adenocarcinoma, 17 cases of metastatic prostatic adenocarcinoma involving lymph nodes and 15 cases of metastatic prostatic adenocarcinoma involving bone. Twenty-eight percent (10/36) of the primary tumors displayed nuclear staining for p53. Increased p53 immunoreactivity was observed in only 6% (1/16) of prostatic adenocarcinomas with a total Gleason score of 6 or less, as compared with 45% (9/20) of those adenocarcinomas with a Gleason score of 7 or more. Fifty-nine percent (10/17) of the lymph node metastases and 43% (6/14) of the bone metastases displayed nuclear immunoreactivity for p53. Our results indicate that increased p53 expression is positively correlated with increased histologic grade and with the presence of metastatic disease in patients with prostatic adenocarcinoma, and they suggest that mutations of the p53 gene may play a role in mediating the behavior of a biologically aggressive subset of this common neoplasm.
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PMID:p53 immunoreactivity in primary and metastatic prostatic adenocarcinoma. 767 61

Abnormalities of the TP53 gene are currently the most common genetic alterations associated with human malignancy. The study of altered patterns of p53 protein expression in primary prostate cancer has to date yielded a much lower incidence of alteration compared to bladder, colon, lung and breast cancer. However, the analysis of prostate cancer metastases has been limited. The objective of our study was to determine the prevalence of p53 nuclear accumulation in primary, metastatic and hormone refractory prostatic adenocarcinoma, and to characterize its relationship with conventional clinicopathological variables. We used 2 antibodies (mouse monoclonal PAb 1801 and rabbit polyclonal CM-1) and an immunohistochemical method in 93 paraffin embedded tumors (48 primary tumors, 29 lymph node metastases and 16 bone metastases) to assess p53 nuclear accumulation. Overall, p53 nuclear accumulation was observed in 19 tumors (20%), including 17 with PAb 1801 and CM-1 immunoreactivities, and 2 with CM-1 immunoreactivity only. The pattern of p53 immunoreactivity was heterogeneous in most tumors, with only 3 cases exhibiting homogeneous staining. Primary, lymph node and bone metastases exhibited p53 nuclear staining in 9 of 48 (19%), 2 of 29 (7%) and 8 of 16 (50%) cases, respectively (p = 0.003). In 6 of 10 primary hormone refractory tumors (60%) and in 3 of 38 primary hormone naive tumors (8%) p53 nuclear immunoreactivity was expressed (p = 0.002). P53 nuclear accumulation was significantly more common in higher grade primary tumors (p = 0.007). Our results suggest that p53 nuclear accumulation is relatively uncommon in prostate cancer. However, p53 nuclear accumulation appears to be associated with advanced stages of disease, as illustrated by its relatively higher occurrence in hormone refractory tumors and bone metastases. Furthermore, the significantly greater prevalence of p53 accumulation in bone metastases is currently the highest reported for prostate cancer.
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PMID:Immunohistochemical determination of p53 protein nuclear accumulation in prostatic adenocarcinoma. 815 73

The progression of prostatic adenocarcinoma from localized disease to metastatic carcinoma appears to be a multi-step sequence. The expression of common oncogenes/oncosuppressor genes and the mediating effect of neuroendocrine tumor cells may play a role in this progression. The expression of the more frequently investigated oncogenes/oncosuppressor genes (p53, c-myc, c-erbB-2, bcl-2) and the presence of neuroendocrine cells were assessed in prostatic cancer tissue from patients with localized and metastatic cancer. These oncogenes/oncosuppressor genes were evaluated according to tumor stage and grade and their relationship to one another. Grade was not related to any of the oncogene markers or to the presence of neuroendocrine cells. Advancing stage was associated with a significant increase in p53 expression, while other markers remained constant in all stages. Neuroendocrine cells, p53, c-myc, c-erbB-2 and bcl-2 were rarely co-expressed at any stage of prostate cancer.
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PMID:Immunohistochemical detection of oncogene proteins and neuroendocrine differentiation in different stages of prostate cancer. 853 88

Prostate cancer is the second leading cause of male cancer deaths in the United States. Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating disease. Prostate secretory epithelial cells and androgen-dependent prostate carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independent and refractory to further therapeutic manipulations during disease progression. Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation. We report the functional definition of a novel genetic locus within human chromosome 10pter-q11 that mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells. A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinoma cell line. Microcell hybrids containing only the region 10pter-q11 were suppressed for tumorigenicity following injection of microcell hybrids into nude mice. Furthermore, the complemented hybrids undergo programmed cell death in vitro via a mechanism that does not require nuclear localization of p53. These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma.
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PMID:Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11. 863 12

The prognostic value of the p53 gene (TP53), the most commonly mutated gene in human cancers, has been well established for several cancer types. However, because varying frequencies of TP53 mutations have been identified in prostatic adenocarcinoma (CaP) by genetic and immunohistochemical (IHC) studies, the role of TP53 in CaP tumorigenesis is currently unresolved. These experimental discrepancies could be caused by tissue heterogeneity within prostatic neoplasms, variations in experimental protocols, or other factors. Thus, the goal of this study was to develop a reliable IHC approach for the detection of p53 in archival prostate tissue. The authors evaluated four p53 antibodies, CM-1, 1801, DO-1, and DO-7, for their ability to reveal p53. They chose two reference CaP cell lines, 26 patient specimens (including eight benign prostatic hyperplasias (BPHs), 16 CaPs, and two lymph node metastases), one prostate and nine kidney cell lines for p53 analysis. The TP53 status of these samples was characterized using single-strand conformational polymorphism (SSCP) analysis of RNA/PCR products and sequencing. IHC detection of p53 was markedly enhanced by using the combination of microwave heat-induced antigen unmasking and a cocktail of the DO-1 and DO-7 antibodies. This approach identified 14 of 15 (93%) cell lines and patient samples having TP53 missense mutations in the exons 5 to 8 region. Of the 21 patient samples and cell lines that were either normal by SSCP or expressed p53 mutations that are not expected to stain, 18 (86%) were immunonegative. Because of this good correlation between molecular and IHC analysis, this approach may help to resolve the uncertainty about TP53 in CaP tumorigenesis.
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PMID:Correlation of genetic and immunodetection of TP53 mutations in malignant and benign prostate tissues. 866 67

bcl-2, an inhibitor of programmed cell death (apoptosis), is present in high levels in a subset of prostatic adenocarcinomas. In this study, 42 prostatic adenocarcinomas were analyzed to determine whether increased bcl-2 levels are associated with rearrangements in the 2.8-kb major breakpoint region, an association known to occur in certain follicular lymphomas featuring a t(14:18) translocation. Immunostaining for bcl-2 and p53 proteins was performed on formalin-fixed, paraffin-embedded tumor specimens using murine anti-human bcl-2 and p53 monoclonal antibodies in all 42 cases. Genomic DNA from paired frozen samples of each tumor was subjected to digestion with HindIII and EcoRI and the products analyzed on a Southern blot with a 2.8-kb-digoxigenin-labeled major breakpoint region probe. Comparisons between groups were evaluated with the Fisher exact test. Diffuse, strong cytoplasmic immunoreactivity for bcl-2 was present in the epithelial cells of tumor glands in 16 of 42 cases (38%), including 8 of 19 low grade (Gleason score 6 and below) and 8 of 23 high grade (Gleason score 7 and above) prostatic adenocarcinoma. Southern blotting demonstrated a normal 2.8-kb germline DNA fragment in every case, with no evidence of rearrangement. Nuclear p53 staining was present in 10 of 24 high grade and 0 of 18 low grade tumors (P < 0.001). Only four cases exhibited positivity for both bcl-2 and p53, and there was no association of bcl-2 positivity with co-expression of the p53 protein (P = 0.58). We conclude that aberrations in the function of either bcl-2 or p53 could possibly modify the apoptotic pathway resulting in the extended survival of tumor cells. Also, increased bcl-2 levels in prostatic adenocarcinomas occur in the absence of detectable rearrangements in the major breakpoint region.
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PMID:Increased bcl-2 protein levels in prostatic adenocarcinomas are not associated with rearrangements in the 2.8 kb major breakpoint region or with p53 protein accumulation. 882 55


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