P53 Gene In Lung Cancer Research Articles

Exploring the Significance of p53 Gene in Lung Cancer: Etiological Factors, Clinical Implications, and Therapeutic Approaches

Exploring the Significance of p53 Gene in Lung Cancer: Etiological Factors, Clinical Implications, and Therapeutic Approaches

Abstract 2541: Effect of carcinogen acrolein on DNA repair and mutagenic susceptibility.

Abstract Lung cancer death is the number one cause of cancer death in the United States. Cigarette smoking is the major cause of lung cancer. Cigarette smoke (CS) contains more than 60 human carcinogens. Our early work has demonstrated that acrolein (Acr), one of the most abundant aldehydes in CS, reacts with DNA to form α- and α-hydroxy-1, N2-cyclic propano-dG adducts (α-Acr-dG and α-Acr-dG). The distribution of Acr-dG in the p53 gene coincides with lung cancer p53 mutational spectrum. Acr-dG adducts induce mainly G to T and G to A mutations that are similar to the mutation signature found in the p53 gene in lung cancer. We have also found that Acr inhibits DNA repair. Therefore, we concluded that Acr is a major etiological agent for CS related lung cancer. In this study, we found that Acr-dG adducts are poorly repaired in Acr treated normal human bronchial epithelial (NHBE) cells. Intriguingly, NHBE cell lysates are competent in carrying out in vitro repair synthesis assay using Acr-modified as well as UV-irradiated DNA as substrates. These results indicate that Acr treatment impairs DNA repair function. We found that Acr not only inhibits nucleotide excision repair (NER), it also inhibits base excision repair (BER) and mismatch repair (MMR). Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes. However, Acr causes a reduction of XPA, XPC, hOGG1, PMS2 and MLH1 proteins and that this effect can be neutralized by the proteosome inhibitor, MG132. We further found that Acr treatment enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA, but can also modify DNA repair proteins and further cause degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2541. doi:1538-7445.AM2012-2541

P53 mRNA in- Situ Hybridization analysis and Immunohistochemical Expression in Lung Cancer: A Comparative Study.

Background and objectives: P53 gene mutation and deletion are among the important molecular markers linked to lung cancer. In most cases, the inactivating mutations affecting both p53 alleles are acquired in somatic cells. Less commonly, the mutations are inherited ones. The aim of the present study was to analyze the frequency of having a wild and/or a mutated p53 gene in lung cancer compared to benign lung lesions and to relate these findings to different morphological types and grades of lung cancer.Patients, materials and methods: In this retrospective study, the histopathology blocks of 30 lung cancer cases covering the period from2002 to 2007were obtained from the archives of the histopathology section of the Special Surgeries Hospital Laboratories. Twenty cases of non-malignant lung diseases served as a control group. Sections made on charged slides were subjected to p53 mRNA in-situ hybridization and p53 protein immunohistochemical staining.Results: Positive p53 in situ hybridization signal was detected in 29 cases of carcinoma. The highest percentage score was score- 3 being detected in 16(53.3%) cases. High intensity of hybridization signal was seen in 17(56.7%) cases. All control cases revealed positive hybridization signals (100%). Seven cases revealed score-3 and of these 5 revealed high intensity of hybridization. Immunohistochemical expression of p53 protein was seen in 21(70%) cases of carcinoma with score-3 being found in 11(36.7%) cases, 7cases revealed score-3 in situ hybridization signals as well. High intensity was found in 11(36.7%) cases, 10 of them showed high intensity of hybridization signal. Only two control cases (10%) revealed positive p53 expression. They showed score-2 and low intensity of expression. Significant statistical correlations were found between in situ hybridization signaling and immunohistochemical expression scores and intensities in carcinoma cases with p value < 0.05.Conclusion: The relations of tumor grade to the score and intensity of ISH signaling and IHC expression were significant suggesting the importance of having higher scores and intensities of positive cells which is an indication of tumor progression and prognosis. Studying p53 gene integrity or expression of a mutated protein is important for predicting tumor prognosis and establishing a proper therapeutic approach.

Three new regions on chromosome 17p13.3 distal to p53 with possible tumor suppressor gene involvement in lung cancer.

We investigated loss of heterozygosity (LOH) at the distal portion of the p53 gene on the short arm of chromosome 17 in lung cancers in order to search for new tumor suppressor genes. The roles of the putative genes were also studied in terms of pathological features. One hundred and forty‐five resected non‐small cell lung cancers were examined for LOH using 11 markers mapped on, and distal to the p53 locus, and deletion maps were constructed. Four commonly deleted regions were found: one from TP53 to ENO3, where the p53 gene resides, and three others from ENO3 to D17S1566, D17S379 to D17S1574 and distal to ABR, with LOH frequencies almost the same as, or higher than, at the TP53 locus. Examination of the relationship between LOH of the latter three regions and histopathological parameters of adenocarcinomas (genetically negative for p53 mutation) revealed allelic losses on D17S379 to be associated with advanced lesions, while D17S513 was more frequently deleted in poorly differentiated tumors. These results indicate that new tumor suppressor gene(s) may reside on these three distinctly deleted regions on chromosome 17p13.3 distal to the p53 gene in lung cancer, with possible roles in progression and differentiation of adenocarcinomas.

The role of p53 gene in lung cancer with special emphasis on hereditary types

Lung cancer is the most common type of cancer affecting men and the fifth most frequent female cancer. The survival rate related to lung cancer is low, with the 5-year survival amounting to 10–13% in highly advanced countries. In Poland lung cancer survival does not exceed 5%. The major causes of lung cancer incidence include tobacco smoking, environmental factors and genetic predisposition. The most frequent genetic modifications observed in lung cancer cells are mutations in the myc, ras and/or erb1 genes. The p53 gene has been located on the short arm of chromosome 17 and has been found to consist of 11 exons with the first one being non-coding. The analysis of its sequence in different species resulted in identifying five highly conservative regions, including exons 1, 4, 5, 7 and 8. The p53 has been classified as a suppresser gene. The p53 protein is a nuclear phosphoprotein composed of 393 amino-acids. This protein is active in the two most important stages of the cellular cycle: during the transition between phases G1 and S and between phases G2 and M. The function of p53 can be described as ensuring the integrity of the genome by preventing replication of the damaged DNA and cell division. When the repair process fails, p53 triggers the apoptosis of cells. In addition to the regulatory function, p53 acts also as a transcription agent. Mutations in p53 are responsible for 60% of cases of human lung cancer. The mutations are most often found in microcellular lung cancer (70%) and are less frequent in the cases of adenoid lung cancer (33%). The most common mutations related to lung cancers include: transversions of the G:C/A:T type, missense mutations, nonsense mutations and deletions. These mutations occur in as many as 100 various locations but the most characteristic ones for lung cancer are found in codon 157, 248 and 273. The hereditary mutations in p53 are associated with the Li-Fraumeni syndrome. This syndrome indicates a higher risk of developing different forms of cancer, including lung cancer. Genetic testing aimed at identifying the carriers of p53 mutations should be limited only to high-risk groups defined on the basis of a diagnostic pattern proposed by Lynch. In the families with one member affected by lung cancer the risk of developing lung cancer by first-degree relatives is four times higher compared to general population risk.

Mutations in the p53 gene in lung cancer are associated with cigarette smoking and asbestos exposure

It has been proposed that the patterns of mutations in the p53 tumor suppressor gene will provide clues to the mechanisms of cancer occurrence. Cigarette smoking is known to be the greatest risk factor for lung cancer. Epidemiological evidence has also implicated radon and asbestos as exposures that significantly increase this disease risk; asbestos exposure synergistically enhances the lung cancer risk of smokers. Previous studies of the mutational spectra of the p53 gene in lung cancer have shown cigarette smoke and radon exposure to be associated with the induction of particular lesions or classes of lesions. We have investigated the p53 gene in surgically resectable lung cancers in 85 patients from the Massachusetts General Hospital. We found 25 (29%) patients to have somatic p53 mutations in their tumors. The patients with p53 mutations who were current smokers were significantly older (75.1 versus 59.8 years; P < 0.01 and had smoked for significantly more years (56.8 versus 41.2 years; P < 0.01) than had those without p53 changes. Consistent with other reports, we observed a large number (40%) of G:C to T:A transversion mutations, noting that their occurrence increased with increasing cumulative exposure to cigarette smoke. Interestingly, we also found that p53 mutations occurred significantly more frequently in patients with a history of occupational exposure to asbestos [3 of 60 (5%) for patients without p53 mutations versus 5 of 25 (20%) of those with p53 mutations; P < 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormality of p53 gene in lung cancer.

Abnormality of p53 gene in lung cancer.

A Chemical Mismatch Cleavage Method Useful for the Detection of Point Mutations in the p53 Gene in Lung Cancer

Point mutations in genes can be etiologic of pulmonary diseases, as in the case of the inherited disorders alpha-1-antitrypsin deficiency and cystic fibrosis or in the context of dominant and recessive oncogenes in lung cancer. Various methodologies have been developed to screen for single-base mutations. These techniques include direct DNA sequencing, RNase protection, denaturing gradient gel electrophoresis, and chemical mismatch cleavage. The latter method offers the advantages of rapid and efficient analysis of genomic or cDNA and is thus ideally suited to screening applications. Furthermore, all possible single-base changes can theoretically be detected. In the present work, chemical mismatch cleavage was utilized to detect mutations in the p53 gene in small cell and non-small cell lung cancer. This technique was modified by using a two-step, hemi-nested PCR procedure for preparation of target genomic DNAs permitting an expanded target size for analysis. Evaluation by chemical mismatch cleavage of eight p53 cDNAs derived from lung tumors shown to have different mutations by DNA sequencing correctly detected the presence of a point mutation in all instances. Analysis of six additional tumor genomic DNAs with defined mutations in the corresponding p53 cDNAs accurately confirmed the mutation at the level of the genome. The technique also identified codon 72 and intron 6 polymorphisms. Using the intron 6 polymorphism, loss of heterozygosity at the p53 locus in tumor DNA was readily detected by chemical mismatch cleavage. Finally, utilizing this technique for scanning analysis of the p53 gene of uncharacterized lung tumor DNAs, additional mutations were identified in a prospective manner which were confirmed by sequence analysis.(ABSTRACT TRUNCATED AT 250 WORDS)