Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For lung cancer diagnosis, the diagnostic significance of the ras, myc, erbB2 oncogenes, and the p53 anti-oncogene was reviewed. Point mutation of the ras oncogene, amplification of the myc oncogene, and overexpression of the erbB2 oncogene are associated with poor prognosis of lung carcinomas. Mutation of p53 anti-oncogene is a common event of lung carcinoma and the differences in its mutation pattern can be used for the molecular diagnosis of multicentric lung carcinomas.
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PMID:[Molecular diagnosis of lung carcinoma]. 817 43

The genes regulated by p53, as well as the factors modulating its function, need to be identified before the mechanism of action of p53 in control of cell growth can be adequately understood. Binding of the SV40 large T-antigen protein to an evolutionally conserved (conformational) domain of p53 inhibits p53's DNA-binding and transcription activation activities. Cellular proteins might also bind to this same region of p53 to regulate its function. A hybrid protein composed of protein A fused to the conformational domain (amino acids 115-295) of p53 was expressed in Escherichia coli and used as an affinity probe for binding proteins in detergent lysates of non-small cell lung carcinoma (NSCLC) cells. The wild-type p53 hybrid protein associated with several major proteins of molecular weights 45 K, 56 K, and 70 K, as well as other minor species ranging in molecular weight from 30 K to 90 K. These proteins bound specifically to the p53 sequence of the hybrid protein. Protein A did not associate with these proteins and the two p53 hybrid proteins containing missense mutations at codons 273 and 175 exhibited a 40-80% weaker association. In addition, T antigen competed with the cellular proteins for binding to the conformational domain. The conditions of cell growth had a profound effect on the expression of the p53 binding proteins. Considerably more p53 binding proteins were expressed in actively growing cells than in cultures maintained under conditions for slow growth. Quantitative differences in expression of p53-binding proteins were observed among different NSCLC cell lines. The expression of p53-binding proteins was not restricted to NSCLC cell lines; detergent extracts of an osteosarcoma cell line yielded similar p53-binding proteins.
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PMID:Binding of cellular proteins to a conformational domain of tumor suppressor protein p53. 824 46

The structure and the function of the p53 gene were studied in two metastatic cell variants derived from Lewis lung carcinoma. Single missense mutation at codon 334 was detected in the p53 gene of both cell variants. In spite of the identical mutation, the in vitro and in vivo growth rates of the two cell variants were differentially affected by the constitutive expression of exogenous wild-type (wt) p53 gene. In fact, only the more malignant cell line (C87) was severely affected by the wt-p53 gene introduction. However, the in vivo effects on this cell line were transient because during serial in vivo passages, cell populations lacking the wt-p53 gene were selected. Genetic mechanisms responsible for the resistance of the less metastatic cell variant (BC215) to the wt-p53 expression, were investigated. Intrinsic ability to mutate exogenous cDNA sequences was tested. We report that BC215 cells continued to express exogenous wt-p53 sequences after several in vitro passages. The expression of mdm2 gene was evaluated. The data demonstrated that BC215 cells constitutively express higher levels of mdm2 gene than C87 cells. We conclude that the overexpression of this gene might be responsible for the resistance of BC215 cells to exogenous wt-p53 gene expression.
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PMID:Wild-type p53 differentially affects tumorigenic and metastatic potential of murine metastatic cell variants. 837 12

A series of 112 patients operated for non-small cell lung cancer was analyzed retrospectively. Nuclear suspensions were prepared from formalin-fixed, paraffin-embedded biopsies, and DNA content was measured simultaneously with p53 expression using flow cytometry. The expression of p53 protein was determined by the monoclonal antibody PAb 1801, which recognizes both wild-type (normal) and mutated forms of p53. By the level of p53 expression, four patient groups were statistically defined. Patients in the two groups with no detectable and extremely high p53 expression had a significantly better prognosis than patients in the two groups with moderately increased p53 expression. By logistic regression, p53 expression was found to be the single best predictor of 5 year survival. Patient age and tumor stage were less important prognostic factors. No difference in 5 year survival was observed between diploid and aneuploid tumors. We conclude that p53 is a useful prognostic predictor in low stage non-small cell lung carcinoma using the monoclonal antibody PAb 1801. The applicability of this antibody to archival material in flow cytometric analysis should allow a broad range of tumor types to be analyzed with respect to the prognostic significance of p53 overexpression.
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PMID:Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas. 839 Dec 42

To establish a genetic model of the progression of head and neck squamous carcinoma we have defined the incidence and timing of p53 mutations in this type of cancer. We sequenced the conserved regions of the p53 gene in 102 head and neck squamous carcinoma lesions. These included 65 primary invasive carcinomas and 37 noninvasive archival specimens consisting of 13 severe dysplasias and 24 carcinoma in situ lesions. The incidence of p53 mutations in noninvasive lesions was 19% (7/37) and increased to 43% (28/65) in invasive carcinomas. These data suggest that p53 mutations can precede invasion in primary head and neck cancer. Furthermore, the spectrum of codon hotspots is similar to that seen in squamous carcinoma of the lung and 64% of mutations are at G nucleotides, implicating carcinogens from tobacco smoke in the etiology of head and neck squamous carcinoma.
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PMID:The incidence of p53 mutations increases with progression of head and neck cancer. 840 17

It is known that transfer of the wild-type p53 gene into p53-negative cells from transgenic mice increases their sensitivity to drug and radiation-induced apoptosis. However, unlike many human tumors, these transgenic cells do not express mutant p53, and it is not known from these earlier studies whether wild-type p53 dominates the effects of mutant p53 with respect to drug and radiation sensitivity. We addressed this question in glioblastoma, a disease characterized by an unusually high level of intrinsic resistance to therapy and poor prognosis: mean survival time from diagnosis is only about 1 yr. We introduced the gene for wild-type p53 into human T98G glioblastoma cells, which express endogenous mutant p53 but not wild-type p53. Stable transfectants that co-expressed mutant and wild-type p53 had enhanced sensitivity to cisplatin and gamma radiation, compared with parental cells, control vector-transduced cells, and transduced cells that had lost expression of wild-type p53. Transient wild-type p53 expression after high-efficiency gene transfer by a p53 adenovirus also sensitized the cells to cisplatin and correlated with the induction of apoptosis. The sensitization effect was also observed in p53 adenovirus-infected H23 small cell lung carcinoma cells, which express endogenous mutant p53. Therefore, wild-type p53 gene transfer has dominant effects over mutant p53 in sensitizing tumor cells to therapy, which supports the potential of p53 gene therapy to enhance the efficacy of traditional therapy.
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PMID:Use of wild-type p53 to achieve complete treatment sensitization of tumor cells expressing endogenous mutant p53. 851 17

In the present study the prognostic significance of accumulation of nuclear p53 protein on survival and freedom from local progression was investigated. Formalin-fixed, paraffin-embedded sections obtained by bronchoscopy or mediastinoscopy were used to examine the expression of nuclear p53 protein using immunohistochemistry. In 37 cases (57%), overexpression of the p53 protein was detected. No relation was found between p53 expression and other pretreatment variables. Response to radiotherapy was found in 11 p53-negative cases (65%) versus 10 p53-positive cases (42%). Freedom from local progression was significantly better in the p53-negative cases as compared with the p53-positive cases. The p53-negative cases who responded to radiotherapy showed an excellent freedom from local progression rate after 2 years of 100%, whereas all p53-positive cases without response to radiotherapy showed local progression within 24 months. Overall survival between p53-negative and -positive cases did not differ, however the disease-specific survival was found to be worse in the p53-positive cases as compared to the negative cases (median survival 8.4 vs. 14.4 months (P < 0.05)). No correlation was found between p53 expression and the frequency of distant metastases. In conclusion, the results of this study suggest that p53 protein expression may be of prognostic value on freedom from local progression in non-small cell lung carcinoma.
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PMID:The prognostic significance of accumulation of p53 protein in stage III non-small cell lung cancer treated by radiotherapy. 853 9

Accumulation of the tumour suppressor gene p53 product due to a gene mutation is frequently seen in human carcinomas, including lung carcinoma. Another indirect mechanism involving p53 in malignant growth relates to the E6 protein of the human papillomavirus (HPV), which is able to bind and degrade wild-type p53 protein, thus eliminating its tumour suppressor activities. Bronchiolo-alveolar carcinoma (BAC) is a rare type of lung carcinoma. The aim of our study was to examine the occurrence of p53 accumulation and the presence of HPV DNA in BAC. Sections of 22 BACs were immunohistochemically stained using a p53 antibody, CM-1. The presence of HPV DNA in BACs was verified by in situ hybridisation for HPV types 6, 11, 16, 18, 31 and 33 and confirmed by PCR. Thirty-six percent of the tumours showed abnormal p53 nuclear accumulation, and HPV DNA, revealed by in situ hybridisation, was found in 36%. Unexpectedly, only 13% of the type 1 BACs were positive for p53, whereas 45% of the type 2 BACs were positive. During a follow-up of 12-176 months, only 10% of the patients with BACs negative for both p53 and HPV died of the disease, compared with 42% of the patients with either p53 or HPV positivity. No inverse relationship between abnormal p53 protein accumulation and the presence of HPV DNA was found.
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PMID:p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis. 855 Feb 45

Lung resections from 50 Chinese patients in Hong Kong diagnosed as having non-small cell lung carcinoma were examined for the presence of mutations in the p53 gene by polymerase chain reaction single-stranded conformation polymorphism methods and for aberrant protein expression by immunostaining techniques. Eight-point mutations in the evolutionarily conserved exon 5 through 8 regions were detected. Abnormal expression of p53 detectable by immunostaining techniques was seen in 23 specimens tested. There was no statistically significant correlation between the detection of p53 aberrations and age, sex, smoking history, histologic type, and tumor stage. Aberrant p53 protein levels detectable by immunostaining were significantly associated with the clinical and nodal staging of the tumors.
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PMID:p53 mutations in non-small cell lung carcinomas in Hong Kong. 861 82

Neuroendocrine tumors of lung, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC) constitute a spectrum of malignancies in which the pathologist at times has difficulty in discerning tumor subtype and aggressiveness in a reproducible fashion. Therefore, 59 primary neuroendocrine lung tumors including 10 TCs, 26 ACs, 15 LCNECs, and 8 SCLCs were selected from cases collected from 1976 to 1988 and immunostained for p53 protein. All of these tumors were also genotyped for specific point mutational damage affecting p53 (exons 5, 7, and 8; with ACs additionally sequenced for p53 exon 6); 13 tumors for K-ras-2 (exon 1); and 31 tumors for c-raf-1 (exon 15) growth-regulatory genes. Genotyping was performed on topographically selected, minute tumor samples removed from unstained formalin-fixed, paraffin-embedded tissue sections (topographic genotyping) using polymerase chain reaction and direct sequencing. The distribution of p53 immunohistochemical staining had four patterns: negative in TCs, one-half of ACs, 3 of 15 LCNECs, and 1 of 8 SCLCs; less than 10% but more than five tumor cells per 10 high power fields (focal) in a subset (7 of 26) of aggressive ACs; 10 to 49% of tumor cells (patchy) in a subset (6 of 26) of ACs with a higher grade of aggressiveness; and 50 to 100% of tumor cells (diffuse), exclusively seen in LCNECs (12 of 15) and SCLCs (7 of 8). Three patterns of immunohistochemical staining intensity of p53 protein were seen: negative, weak or mild, and moderate to marked. SCLCs and LCNECs accounted for cases of moderate to marked staining and were the only ones to have mutations in p53 exons 5, 7, or 8. No mutations were found in AC and TC, showing absent to weak staining and no staining, respectively. The difference in distribution and staining intensities between LCNEC and SCLC compared with AC and TC was statistically significant (P < 0.001). Patients having AC with patchy p53 immunostaining usually had survival limited to 3 years, whereas those having AC with focal p53 immunostaining subsequently developed metastatic or recurrence of AC disease (P < 0.05). The absence of point mutations in cases with patchy or focal immunostaining suggests increased expression of wild-type p53 tumor suppressor protein likely in response to growth deregulation in a more aggressive subtype of AC. A novel hypothesis is presented in regard to these findings. K-ras-2 and c-raf-1 gene sequence analysis showed no evidence of point mutational change in any of the tumors studied. The TC and AC categories are therefore genetically distinct from the higher grade neuroendocrine SCLC and LCNEC. Immunohistochemistry for p53 on AC lung tumors may be helpful to delineate cases at higher risk for aggressive behavior. Additionally, although LCNEC is categorized as a non-small-cell carcinoma, it is more akin genetically and immunohistochemically to SCLC.
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PMID:Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. 862 22


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