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)

Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression.
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PMID:Oncogenes in human testicular cancer: DNA and RNA studies. 182 52

Using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis, p53 gene mutation was examined in 12 intracranial germ cell tumors (5 yolk sac carcinomas and 7 germinomas), many of which were derived from young patients in the first to the second decade. A total of 10 mutations were detected in 4 of the 12 cases and, in 3 of them, the mutations were multiple or tandem. Among the 10 mutations, 7 were missense, 1 was splicing and 2 were silent. The 7 missense mutations were located at previously proposed hot spot codons or in their vicinity or, when outside the hot spots, at a codon encoding an amino acid conserved in most vertebrates. These findings suggested that all 7 missense mutations may actually give rise to functional alteration of the p53 protein. The splicing mutation was considered to be a germ-line mutation, though its biological effect was equivocal, since the neoplastic tissue contained an additional mutation. The pattern of the mutations was predominancy of G:C-A:T transition with frequent involvement of the CpG site. These mutations were more frequently detected in yolk sac carcinomas (60%; 3/5 cases) than in germinomas (14%; 1/7 cases), suggesting that the contribution of the p53 mutation to carcinogenesis differed with the histological type of the intracranial germ cell tumor.
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PMID:Intracranial germ cell tumors: detection of p53 gene mutations by single-strand conformation polymorphism analysis. 762 20

P53 tumor suppressor gene protein immunostaining was evaluated in the primary tumor of adult testicular germ cell cancer to assess if P53 expression would serve as a clinically useful tumor marker. Representative archival tissues from 152 orchiectomy specimens were studied for P53 immunohistochemistry. Seminoma and nonseminomatous germ cell tumor constituents revealed P53 expression via immunohistochemistry in 90% and 94% of the cases, respectively. For seminoma, there was a trend toward decreased P53 expression with advancing stage. For nonseminomatous germ cell tumor, although all cellular components showed variable P53 expression, P53 expression in embryonal carcinoma constituents increased among stages of disease. A third of pathological stage I cancer patients exhibited 2+ or greater P53-embryonal staining compared with 61% with stage II (p = 0.0670) and 67% with stage III (p = 0.0815) disease, respectively (Kruskal-Wallis, 2-sided test). As a secondary objective, we wanted to determine if P53 immunohistochemistry would be useful to predict occult disease in clinical stage I nonseminomatous germ cell tumor. This group was studied for P53-embryonal immunohistochemistry, the presence of vascular invasion and the quantitative determination of percentage of embryonal carcinoma in the primary tumor in a multivariate fashion to assess if these tests could be clinically useful to predict occult disease. Degree of P53 immunostaining of the embryonal component in the primary tumor was statistically greater for stage II by univariate logistic regression analysis (p = 0.0362). Similarly, the per cent embryonal cancer (p = 0.0002) and vascular invasion (p = 0.0005) were highly significant as predictors of occult stage II disease via the univariate testing. By multivariate logistic regression analysis, the model consisting of per cent embryonal cancer and vascular invasion provided the best prediction of occult disease in the clinical stage I cohort. In addition, this model had the highest sensitivity and specificity of all multivariate models considered. The addition of P53-embryonal staining did not improve predictability nor sensitivity/specificity. The P53 tumor suppressor gene protein is expressed to some degree in most testicular germ cell tumors and degree of staining/expression varies according to stage of disease. From the standpoint of a clinically useful primary tumor risk factor for predicting occult disease, vascular invasion by the tumor and percentage of embryonal carcinoma component in the tumor are more useful than P53 immunohistochemistry.
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PMID:Immunohistochemical expression of P53 tumor suppressor gene protein in adult germ cell testis tumors: clinical correlation in stage I disease. 801 85

This study investigates the extent of apoptosis in 53 testicular and ovarian germ cell tumors by using the in situ 3'-end DNA labeling technique on tumor sections. The tumors were also immunostained with antibodies to the p53 and bcl-2 proteins. The extent of apoptosis was highest in embryonal carcinoma (mean, 2.9%) followed by seminoma (mean, 1.1%), choriocarcinoma (mean, 0.7%) and immature teratoma (mean, 0.7%). In individual components of the mixed germ cell tumors the apoptotic index was in the same range as in the corresponding pure germ cell tumors. Mature teratomas rarely contained any apoptotic cells. Sixty-two percent of all the tumors expressed p53 protein. p53 expression was quantitatively strongest in embryonal carcinomas which also showed the highest level of apoptosis. Bcl-2 positivity could only be detected in some mesenchymal and epithelial components of the immature and mature teratomas; embryonal carcinomas, seminomas, or choriocarcinomas did not express bcl-2 at all. Our results show that the level of apoptosis in germ cell tumors associates with the histological type of the neoplastic component independent of whether it is singly present or a component of a mixed germ cell tumor. The results suggest that the quantity of p53 expression may contribute to the level of apoptosis in different tumor groups.
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PMID:Extent of apoptosis in relation to p53 and bcl-2 expression in germ cell tumors. 891 34

Congenital sacrococcygeal teratoma (SCT) is the most common germ cell tumor of infancy and childhood with a female preponderance. Most SCTs are diagnosed at birth, are benign, and consist of fully differentiated, mature tissues. Tumorigenesis of SCTs remains poorly understood. Almost nothing is known about possible oncogene activation or tumor suppressor inactivation in these rare tumors. We describe the presence of various oncoproteins and tumor suppressor proteins in eight cases of congenital SCT. The following oncogenes were examined: ras family (c-H-, c-N-, and c-K-ras), early genes (fos, jun), and tumor suppressor genes (p53 and nm23-H-I). There was no relationship between the intensity of expression of these oncoproteins and tumor suppressor genes and the following parameters: tumor size, age, and survival of the patients. We did not observe any difference, however, between the expression of the examined oncogenes and tumor suppressor genes nm23 and p53 in immature and mature teratomas. Our findings suggest that the ras family of oncogenes, fos and jun oncogenes, and nm23 and p53 tumor suppressor genes are present in congenital SCT, indicating a possible role in genesis and development of these tumors.
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PMID:Oncoproteins and tumor suppressor proteins in congenital sacrococcygeal teratomas. 905 59

Adult human male germ cell tumors (GCTs) arise by transformation of germ cells (GCs). The transformed GCs exhibit pluripotentiality to differentiate into embryonic, extra-embryonic, and somatic tissue types, and are highly sensitive to cisplatin-based chemotherapy. Recent investigations into the genetics of GCTs have advanced methods of diagnosis and provided leads to the understanding of molecular basis of transformation, differentiation, and sensitivity/resistance. Cytogenetic and molecular cytogenetic studies have identified multiplication of 12p, manifested in i(12p) or tandem duplication of 12p, as a unique change in GCTs which serves as a diagnostic marker. Ectopic over-expression of cyclin D2, a gene mapped to 12p, as early as in carcinoma in situ identifies a candidate gene in GC transformation. Genetic alterations identified in the tumor suppressor genes deleted in colorectal cancer, retinoblastoma 1 and non-metastatic protein 23 (NME) in GCT suggest that their inactivation play a key role in transformation or differentiation. A number of regions of chromosomal deletion have been identified including those previously known to be deleted in various tumor types and novel candidate tumor suppressor gene sites such as 12q13, 12q22, and 5p15.1-15.2. Identification and characterization of the genes in these sites will provide important clues in understanding the biology of GCT. The molecular studies have also enumerated several possible differentiation controls such as switching of KIT and mast cell growth factor gene expression in a lineage-associated manner, and loss of certain types of genes such as NME in teratomas that may act in a dominant negative fashion in differentiation. The exquisite sensitivity of these tumors to chemotherapy is reflected in their over-expression of wild-type p53 protein and lack of TP53 mutations. These data indicate that multiple genetic events play a role in distinct pathways in the development of GCT, and further elucidation of the underlying genetic and biochemical mechanisms is central to unraveling biology and improving treatment of GCT.
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PMID:A genetic perspective of male germ cell tumors. 956 46

Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to treatment in 20-30% of metastatic lesions remains to be identified. Unlike other solid tumors, no mutations in the TP53 gene have been identified to date in random panels of GCT specimens, which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or subsequently relapsed and resulted in the death of the patient, we have now identified a subset of tumors to contain TP53 mutations within exons 6-9. A cell line derived from one of these tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin in vitro in comparison to a cell line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene.
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PMID:Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. 962 May 51

The Kirsten-ras (onco)gene codes for a GTP-binding membrane protein that is involved in signal transduction. Activated ras triggers a cascade of protein-phosphorylations that ultimately lead to cell proliferation. Ras-mutations are the main cause for adenocarcinomas of the pancreas besides some mutations in the tumor suppressor gene p53 and the c-erbB-2 oncogene. The site of ras mutations in pancreatic cancer is restricted to codon 12 that normally encodes a glycine. For analysis of codon-12 mutations, DNA is extracted from cells in pancreatic fluid and amplified by PCR. Because most of these cells originate from normal tissue with only a few tumor cells in the fluid, "enrichment PCR" must be utilized: In a first round of the PCR, ras sequences from all cells are amplified. By utilizing an appropriate restriction enzyme, wild-type sequences can be digested and the remaining fragments containing mutated sequences be amplified again. An artificial restriction site must be introduced by the 5'primer (...GGA CCT GGT...) for an enzyme (BstNI) (5'CC!WGG 3') to differentiate between wild-type sequence (...GGA GCT GGT...) (during amplification, the G is replaced by a C) and mutated sequences (_...GGA GCT (GTT), (CGT), (CCT), etc.). The necessary manipulations pose a considerable risk for contamination for the second round of the PCR procedure. Therefore, we considered whether it would be feasible to perform the restriction digest simultaneously with the first PCR reaction, and avoiding the second round altogether. The results of our experiments demonstrate that one tumor cell in 1000 normal cells can be determined readily, paralleling the results with the original two step-assay. The restriction enzyme used to enrich mutated sequences is stable long enough to be included into the PCR procedure. By this, wild-type sequence amplicons are digested while they are formed and mutated sequences can be enriched selectively.
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PMID:Restriction digest PCR (RD-PCR) for the analysis of gene mutations. Application to Ki-ras. 980 67

The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA-->GTA mutation at codon 1296 (Ala-->Val), and another case had double point mutations at codons 1472 (GTA-->ATA, Val-->Ile) and 1495 (AGT-->GGT, Ser-->Gly). Miscoding beta-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT -->TTT, Ser-->Phe) and another at codon 37 (TCT-->GCT, Ser-->Ala). Adenomatous polyposis coli (APC) gene and beta-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.
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PMID:APC mutations in sporadic medulloblastomas. 1066 72

To study the relationship of P53 protein expression with clinical course and prognosis in malignant germ cell tumor of ovary P53 protein expression was examined by immunohistochemical ABC methods in 82 cases of the neoplasm and 20 cases of normal ovary tissue. The results showed that no expression of P53 protein was detected in normal ovarian tissue. The total expression rate of P53 protein was 24.39% in neoplasm, and the expression was not significantly correlated with the different histological types of neoplasm. The study however found that the protein expression of p53 gene was significantly correlated with the clinical stages and prognosis of the neoplasm.
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PMID:[P53 protein expression in malignant germ cell tumor of ovary and its relationship with clinical course and prognosis]. 1068 59


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