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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities of the p53 oncogene in lung cancer have recently been reported to be more frequent in small cell lung cancer (SCLC) than in non-small cell lung cancer (non-SCLC), but their status in combined type SCLC is as yet unknown. In this study, immunohistochemical analysis using a polyclonal antibody against p53 protein was performed in 12 surgically resected specimens of combined type SCLC. Immunoreactivity of the p53 protein was found in 5 (42%) of the 12 cases, and the immunostaining pattern of the p53 protein in areas of the non-small cell carcinoma type was the same as in those of the small cell carcinoma type. Thus, it seems that the incidence of p53 abnormalities in combined type SCLC is slightly lower than in ordinary type SCLC. It is also suggested that abnormalities of the p53 oncogene in this histological type may not be a specific event related to the morphological difference between small cell carcinoma and non-small cell carcinoma.
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PMID:p53 immunostaining in combined type small cell lung cancer. Brief report. 754 52

In a previous registry-based survey of 999 patients injected with alpha-emitting 232ThO2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast-administered patients also perpetually exhale 220Rn, a 232Th-daughter. Study of Thorotrast-exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon-associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose-response gradient exists for Thorotrast and malignant mesothelioma.
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PMID:Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: incidence, histology and p53 status. 759 Dec 26

Identification of the genetic alterations that occur in tumors is an important approach to understanding tumorigenesis. We have used comparative genomic hybridization (CGH), a novel molecular cytogenetic method, to identify the gross DNA copy number changes that commonly occur in small cell lung cancer (SCLC). We analyzed ten SCLC tumors (seven primary tumors and three metastases) from eight patients. We found frequent increases in DNA copy number on chromosome arms 5p, 8q, 3q, and Xq and frequent decreases in copy number on chromosome arms 3p, 17p, 5q, 8p, 13q, and 4p. The increase in copy number at 8q24 (MYC) and decreases at 17p13 (TP53), 13q14 (RB), and 3p have previously been identified in SCLC with other methods. Many of the other regions in which we detected common copy number changes have not been reported to be regions of common alteration in SCLC tumors. Comparison of copy number changes between a primary tumor and a metastasis from the same patient showed that they were more closely related to each other than to any of the other tumors. The results of direct CGH analysis of SCLC tumors reported here confirm the existence of copy number changes that we identified previously by using cell lines.
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PMID:Identification of novel regions of altered DNA copy number in small cell lung tumors. 766 37

Small cell lung cancers express neuroendocrine (NE) cell features, while most non-SCLC tumors lack these features. We studied the cytogenetic and genetic alterations in cell lines derived from three unusual subtypes of lung cancer: including carcinoids, non-small cell lung cancers expressing NE properties (NSCLC-NE) and extrapulmonary small cell cancers (ExPuSC) and compared them with those of SCLC and NSCLC lines. Our studies included: cytogenetic studies, restriction fragment length polymorphism (RFLP) analyses with 8 probes spanning commonly deleted loci on chromosomes 3p, 13q and 17p, retinoblastoma gene product (RB) expression, and mutations in the ras and p53 genes. We also summarize previously published data on in vitro chemosensitivity patterns and MDRl gene expression. Our studies demonstrate that all three of the NE cell subtypes have their own distinctive genotypes and phenotypes, each having some similarities and dissimilarities with SCLC and NSCLC.
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PMID:Molecular genetic characterization of neuroendocrine lung cancer cell lines. 776 88

We have performed a comprehensive analysis of the DNA copy number changes that occur in 18 small cell lung carcinoma cell lines using comparative genomic hybridization (Kallioniemi et al., Science (Washington DC). 258: 818-821, 1992). DNA copy number abnormalities detected in this study include previously identified increases at 1p22-32 (L-myc), 2p24-25 (N-myc), and 8q24 (c-myc) and decreases at 17p13 (p53), 13q14 (RB), and 3p. In addition, novel DNA copy number increases were detected at 5p, 1q24, and Xq26, and novel decreases were found at 22q12.1-13.1, 10q26, and 16p11.2. Many of the most common DNA copy number changes revealed are at loci not previously recognized to be important in small cell lung cancer. In addition, a number of the DNA copy number changes, including increases at 1p22-32, 2p24-25, and 3q22-25 and a decrease on 18p, were found to occur preferentially in small cell lung carcinoma lines of the "variant" phenotype. This correlation suggests that genes may reside at these loci whose overexpression or inactivation contributes to the radiation resistance or aggressive growth phenotypes characteristic of this subtype of small cell lung carcinoma.
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PMID:Identification of frequent novel genetic alterations in small cell lung carcinoma. 792 22

p53 mutations and myc gene amplification and expression were studied in 119 lung carcinomas of all histological types. A mutant p53 immunophenotype was previously found in 47% of these tumors by immunohistochemical analysis. Seven cases exhibited p53 genomic rearrangements on Southern blots. Elevated levels of p53 transcript were found in 12 carcinomas (10%) and decreased levels in 27 carcinomas (23%) on Northern blots. In most of the cases, low levels of transcript were associated with negative immunostaining, whereas elevated levels of mRNA were related to positive immunostaining (mutant immunophenotype). p53 RT/PCR analysis in 10 tumors with absence of transcript on Northern blots revealed only weak or absent expression of normal and/or altered size transcripts. These abnormal transcripts showed deletions, insertions or splicing abnormalities. Taken together, p53 abnormalities were found in 66% of lung carcinomas [52% of neuroendocrine (NE) carcinomas and 75% of NSCLC]. c-myc was found to be activated in 24% (10/42) of these NE and in 48% (33/69) of these NSCLC carcinomas using Southern- and Northern-blot techniques. In addition, L- and N-myc genes were also activated in 26% (10/42) of NE carcinomas. No correlation was found between p53 mutations and myc activation in SCLC or in NSCLC, but their association was significantly more frequent in NSCLC than in SCLC. These results indicate that the p53-positive immunophenotype uncovers the occurrence of p53 point mutations in lung cancer and that p53 and c-myc gene alterations are important but represent independent occurrences in the development of lung tumors.
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PMID:p53 genetic abnormalities and myc activation in human lung carcinoma. 801 12

Small cell lung cancer (SCLC) is known to express the HuD protein, the neuronal antigen homologous to Drosophila Elav and Sxl genes involved in neuronal and sex development. HuD is the target of an immune response including high titered antibodies causing paraneoplastic encephalomyelitis and sensory neuropathy. Because the p53 recessive oncogene is mutated and anti-p53 antibodies frequently occur in cancer patients, we wondered if the development of anti-HuD antibodies signaled the presence of HuD mutations in lung cancer. The HuD gene was mapped to chromosome region 1p using a human-mouse hybrid cell panel. We confirmed that 26 of 46 cancer (43 lung cancer and 3 mesothelioma) cell lines expressed HuD mRNA and that this expression, as well as protein expression by Western blot, correlated strongly with the SCLC neuroendocrine phenotype. Southern blot and single-strand conformation polymorphism analyses showed that HuD was not mutated in 78 lung cancers, including patients with the severe paraneoplastic syndrome. Northern blot analysis showed that lung cancer cell lines expressed two major mRNAs (4.3 and 4.0 kilobases) of HuD. We found the three previously described alternative spliced mRNA forms (HuDpro, HuD, and HuDmex). In addition, we also found HuD mRNA had an alternative splicing form in its 5'-coding region. This alternative splice introduced 87 base pairs of sequence and a termination codon resulting in a predicted small, truncated protein (11 amino acids) reminiscent of the male-specific truncated protein in the Sex-lethal (Sxl) gene of Drosophila. However, mRNAs encoding both full-length and truncated proteins were expressed in all SCLCs. These results show that the HuD gene is not mutated in lung cancer, including tumors from patients producing anti-HuD antibodies, but HuD expression is an independent marker or determinant of the neuroendocrine differentiation seen in SCLC.
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PMID:Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines. 806 66

p53 is a tumor suppressor gene, located in the short arm of chromosome 17, which encodes for a nuclear protein involved in the control of cellular growth. Mutations in p53 gene are the most common genetic alterations in a several human cancers, including Non Small Cell Lung Cancer (NSCLC). However, up to now, the role of p53 in the tumour's behaviour and its progression has not been completely clear. We performed immunohistochemical staining for mutated p53 using two monoclonal antibodies, PAb1801 and PAb240, in fresh tumour specimens from 103 consecutive patients who underwent surgery for resectable NSCLC. PAb1801 detects both the normal and mutant form of p53, while PAb240 is specific only for the mutant form and recognizes a denaturation-resistant epitope located between aminoacids 156-335. Both antibodies showed a mainly nuclear staining in neoplastic cells but not in surrounding uninvolved lung tissues. 68 out of 100 (68%) and 37 out of 103 (35.9%) of the cases were positive with PAb1801 and with PAb240, respectively. Tumours from patients with hilar-mediastinal lymph node involvement showed a higher p53 expression, detected by PAb1801, than those without nodal metastases (p = 0.04). Moreover, tumours expressing more than 60% of positive cells with both antibodies showed a significant increase of nodal involvement (p = 0.1; p = 0.03). Furthermore, p53 expression was significantly related to post-surgical stage (p Tumor Stage) (p = 0.04). In addition, we did not find any correlation between p53 expression and proliferating activity evaluated by PCNA, Ki-67 and DNA flow cytometric cell cycle. In conclusion, the evaluation of p53 oncogene expression may identify individuals whose resectable NSCLCs have a more aggressive tumour behaviour.
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PMID:p53 expression in non small cell lung cancer: clinical and biological correlations. 810 Apr 13

Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. The morphological changes progress from hyperplasia, to metaplasia, to dysplasia, to carcinoma in situ, to invasive cancer and finally to metastatic cancer. Multiple molecular changes have been documented in lung cancers, both small cell (SCLC) and non-small cell (NSCLC) types. The number of changes has been estimated to be in double digits. How can so many changes develop in one cell? One possible explanation is the "field cancerization" theory, that states that all or much of the aerodigestive tract epithelium has been mutagenized, perhaps as the result of exposure to tobacco products or other carcinogens. The molecular changes include activation of dominant oncogenes (myc family, K-ras and HER/2/neu genes), as well as loss of recessive growth regulatory genes or anti-oncogenes (p53, and rb as well as unidentified gene or genes on chromosome 3). However, cytogenetic and molecular genetic studies indicate that multiple other specific sites of actual or potential DNA loss may be present in lung cancers. Many of the well characterized molecular changes may function as negative prognostic factors for survival in subsets of lung cancers. Other changes may include development of drug resistance, and production of growth factors and their receptors. It is tempting to associate specific molecular changes with specific morphological changes, as has been attempted in the colon. However, because of the difficulties in serially sampling the respiratory tract, only a modest amount of data has been collected to date. It appears that deletions of chromosome 3p, hyperproliferation and aneuploidy are early changes, while p53 mutations appear later in the preneoplastic cascade. Documentation of intermediate markers for lung cancer and prospective studies of their prognostic effects will be necessary for the design of rational chemoprevention trials.
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PMID:The molecular and cellular basis of human lung cancer. 816 65

The spectrum of p53 gene mutations was determined in formalin-fixed, paraffin-embedded samples of small-cell lung cancer derived from 28 patients. By direct sequencing of exons 5, 7, and 8, including their flanking intron sequences, 18 mutations were identified in 17 tumors (61%), and in all but two of these the wild type allele was lost. In 8 cases, the mutation detected in the tumor was absent from the corresponding normal tissue, indicating that these mutations were somatically acquired. In two patients, identical mutations were found in the primary tumor and corresponding metastases. In a further case, an intrapulmonary metastasis did not show the mutation detected in the primary tumor. The local distribution of the mutations resembled that reported in non-small cell lung cancer and gave no indication of distinct bot spot regions. G-to-T transversions were the predominant type of mutation, reflecting a possible genotoxic influence of carcinogens contained in tobacco smoke. Mutations were equally distributed among tumors with intermediate and oat cell histology and did not show a significant association to age and gender of the patients. Also, no significant relationship was observed between the presence of a mutation and tumor stage (T, N, M) or survival. However, transitions at CpG dinucleotides were restricted to tumors without detectable metastases at the time of biopsy, whereas all other mutations occurred in metastasizing small cell lung cancer.
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PMID:Mutational spectrum of the p53 gene in human small-cell lung cancer and relationship to clinicopathological data. 838 8


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