• Korean Journal of Clinical Laboratory Science
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• v.55 no.2
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• pp.93-104
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• 2023

This study aimed to identify new markers that cause lung adenocarcinoma by analyzing mutation hotspots for the top five genes with high mutation frequency in lung adenocarcinoma in Koreans by next generation sequencing (NGS) analysis. The association between TP53 mutation types and patterns with smoking, a major cause of lung cancer, was examined. The clinicopathological characteristics of lung adenocarcinoma patients with TP53 P72R SNPs were analyzed. In Korean lung adenocarcinoma cases, regardless of the smoking status, the TP53 P72R SNP was the most frequently occurring mutational hotspot, in which the nucleotide base was transversed from C to G, and the amino acid was substituted from proline to arginine at codon 72 of TP53. An analysis of the clinicopathological characteristics of lung adenocarcinoma cases with TP53 P72R SNP revealed no significant correlation with the patient's age, gender, smoking status, and tumor differentiation, but a significant correlation with low stage (P-value =0.026). This study confirmed an increase in TP53 rather than EGFR, which was reported as the most frequent mutations in lung adenocarcinoma in Koreans through NGS. Among them, TP53 P72R SNP is the most frequent regardless of smoking status.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7413-7417
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• 2014

Background: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. Materials and Methods: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR (AS-PCR). Results: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). Conclusions: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4315-4320
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• 2012

Background: The P53 tumor suppressor gene plays a pivotal role in maintaining cellular homeostasis by preventing the propagation of genome mutations. P53 in its transcriptionally active form is capable of activating distinct target genes that contribute to either apoptosis or growth arrest, like P21. However, the MDM2 gene is a major negative regulator of P53. Single nucleotide polymorphisms (SNP) in codon Arg72Pro of P53 results in impairment of the tumor suppressor activity of the gene. A similar effect is caused by a SNP in codon 31 of P21. In contrast, a SNP in position 309 of MDM2 results in increased expression due to substitution of thymine by guanine. All three polymorphisms have been associated with increased risk of tumorigenesis. Aim of the study: We aimed to study the prevalence of SNPs in the P53 pathway involving the three genes, P53, P21 and MDM2, among acute myeloid leukemia (AML) patients and to compare it to apparently normal healthy controls for assessment of impact on risk. Results: We found that the P21 ser31arg heterozygous polymorphism increases the risk of AML (P value=0.017, OR=2.946, 95% CI=1.216-7.134). Although the MDM2 309G allele was itself without affect, it showed a synergistic effect with P21 ser/arg polymorphism (P value=0.003, OR=6.807, 95% CI=1.909-24.629). However, the MDM2 309T allele abolish risk effect of the P21 polymorphic allele (P value=0.71). There is no significant association of P53 arg72pro polymorphism on the risk of AML. Conclusion: We suggest that SNPs in the P53 pathway, especially the P21 ser31arg polymorphism and combined polymorphisms especially the P21/MDM2 might be genetic susceptibility factors in the pathogenesis of AML.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9171-9176
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• 2014

Aim: P53, the most commonly mutated tumor suppressor gene in all types of human cancer, is involved in cell cycle arrest and control of apoptosis. Although p53 contains several polymorphic sites, the codon 72 polymorphism is by far more common. There are divergent reports but many studies suggest p53 pro/pro SNP may be associated with susceptibility to developing various cancers in different regions of the world. The present study aimed to find any correlation between H. pylori infection and progression of carcinogenesis, by studying apoptosis and the p53 gene in gastric biopsies from north Indian population. Materials and Methods: A total of 921 biopsies were collected and tested for prevalence of H. pylori by rapid urease test (RUT), imprint cytology and histology. Apoptosis was studied by the TUNEL method. Analysis of p53 gene polymorphism at codon 72 was accomplished by PCR using restriction enzyme BstU1. Observation: Out of 921 samples tested 56.7% (543) were H. pylori positive by the three techniques. The mean apoptotic index (AI) in the normal group was 2.12, while gastritis had the maximum 4.24 followed by gastric ulcer 2.28, gastropathy 2.22 and duodenal ulcer 2.08. Mean AI in cases with gastric cancer (1.72) was less than the normal group. The analysis of p53 72 SNP revealed that p53 (Arg/Arg), (Pro /Arg) variant are higher (40.59% & 33.66%) as compared to p53 pro/pro variant (25.74%) inthe healthy population. Conclusions: The North Indian population harbors Arg or Pro/Arg SNP that is capable of withstanding stress conditions; this may be the reason of low incidence of gastric disease in spite of high infection with H. pylori. There was no significant association with H. pylori infection and AI. However, there is increased apoptosis in gastritis which may occur independent of H. pylori or p53 polymorphism.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1603-1609
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• 2014

Background: The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median ranging from 6 months to 11.5 years. TP53 is associated with old age, chemotherapy resistance, and worse OS. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized that both TP53 mutations and SNPs at codon 72 would mimic the literature by occurring in a minority of patients, and conferring a worse OS. Materials and Methods: We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n=10). TP53 PCR sequencing was performed using DNA from bone marrow smears. Analysis was accomplished using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Results: Fewer than half of the patients harbored TP53 mutations (40%). There was no significant difference in OS based on gender, AML history, risk-stratified karyotype, or TP53 mutation. There were possible trends toward improved survival among patients less than 60 (11 vs 4 months, p=0.09), Hispanics (8 vs 1 months, p=0.11), and those not harboring SNP P72R (8 vs 2 months, p=0.10). There was a significant improvement in survival among patients with better performance status (28 vs 4 months, p=0.01) and those who did not have a complex karyotype (8 vs 1 months, p=0.03). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Conclusions: Our study confirms previous reports that poor PS and the presence of a complex karyotype are associated with a decreased OS. In our cohort, TP53 mutations were relatively common, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a possible trend toward worse OS among patients with SNP P72R. Larger studies are needed to validate these findings.

• Tuberculosis and Respiratory Diseases
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• v.56 no.2
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• pp.187-197
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• 2004

Background : Nitric Oxide (NO) is a multi-faceted molecule with dichotomous regulatory roles in many areas of biology. NO can promote apoptosis in some cells, whereas it inhibits apoptosis in other cell types. This study was performed to characterize NO-induced cell death in lung epithelial cells and to investigate the roles of cell death regulators including iron, bcl-2 and p53. Methods : A549 cells were used for lung epithelial cells. SNP (sodium nitroprusside) and SNAP (S-nitroso-N-acetyl- penicillamine) were used for NO donor. Cytoxicity assay was done by MTT assay and crystal violet assay. Apoptotic assay was done by fluorescent microscopy after double staining with propidium iodide and hoecst 33342. Iron inhibition study was done with RBCs and FeSO4. For bcl-2 study, bcl-2 overexpressing cells (A549-bcl-2) were used and for p53 study, Western blot analysis and p53 functionally knock-out cells (A549-E6) were used. Results : SNP and SNAP induced dose-dependent cell death in A549 cells and fluorescent microscopy revealed that SNAP induced apoptosis in low doses but necrosis in high doses while SNP induced exclusively necrotic cell death. Iron inhibition study using RBCs and FeSO4 significantly blocked SNAP-induced cell death. And also SNAP-induced cell death was blocked by bcl-2 overexpression. Finally, we found that SNAP activate p53 by Western blot analysis and that SNAP-induced cell death was decreased in the abscence of p53. Conclusion : In lung epithelial cells, NO can induce cell death, more precisely apoptosis in low doses and necrosis in high doses. And iron, bcl-2, and p53 play important roles in NO-induced cell death.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5415-5420
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• 2013

Background: Cell cycle deregulation is a major component of carcinogenesis. The p53 tumor suppressor gene plays an important role in regulating cell cycle arrest, and mouse double minute 2 (MDM2) is a key regulator of p53 activity and degradation. Abnormal expression of p53 and MDM2 occurs in various cancers including lung cancer. Methods: We investigated the distribution of the p53 Arg72Pro (rs1042522) and MDM2 SNP309 (rs2279744) genotypes in patients and healthy control subjects to assess whether these single nucleotide polymorphisms (SNPs) are associated with an increased risk of lung adenocarcinomas in Chinese female non-smokers. Genotypes of 764 patients and 983 healthy controls were determined using the TaqMan SNP genotyping assay. Results: The p53 Pro/Pro genotype (adjusted OR = 1.55, 95% CI = 1.17-2.06) significantly correlated with an increased risk of lung adenocarcinoma, compared with the Arg/Arg genotype. An increased risk was also noted for MDM2 GG genotype (adjusted OR = 1.68, 95% CI = 1.27-2.21) compared with the TT genotype. Combined p53 Pro/Pro and MDM2 GG genotypes (adjusted OR = 2.66, 95% CI = 1.54-4.60) had a supermultiplicative interaction with respect to lung adenocarcinoma risk. We also found that cooking oil fumes, fuel smoke, and passive smoking may increase the risk of lung adenocarcinomas in Chinese female non-smokers who carry p53 or MDM2 mutant alleles. Conclusions: P53 Arg72Pro and MDM2 SNP309 polymorphisms, either alone or in combination, are associated with an increased lung adenocarcinoma risk in Chinese female non-smokers.

• Journal of Animal Science and Technology
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• v.53 no.4
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• pp.311-317
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• 2011

The aim of this study was to evaluate the association between economic traits of Korean cattle (Hanwoo) and genetic variation in fatty acid binding protein 5 (FABP5) gene within QTL region of carcass weight and marbling score traits on BTA 14. We sequenced for detection of single nucleotide polymorphism (SNP) with 24 unrelated Hanwoo samples and identified four SNPs (-1141A>G, 949A>G, 969A>G and 1085C>G). Relationship between the genotypes of 583 Hanwoo individuals by PCR-RFLP and economic traits were analyzed by the mixed regression model implemented in the ASReml program. As the result of statistical analysis, SNP1 (-1141A>G) showed significant effect (p<0.003) on marbling score (MS) and SNP2 (949A>G) showed significant effect (p<0.034) on eye muscle area (EMA). Further studies are required to validate the significant SNPs in a bigger population, but the SNPs (-1141A>G and 949A>G) of FABP5 could be a genetic marker to estimate molecular breeding value (MEBV) for carcass traits in Hanwoo.

• Journal of Animal Science and Technology
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• v.53 no.1
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• pp.7-13
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• 2011

The aim of this study was to identify the polymorphism on exostosin-1 (EXT1) gene and to associate with economic traits in Hanwoo (Korean cattle). We sequenced for detection of single nucleotide polymorphism (SNP) with 24 unrelated individuals and identified four SNPs (T272196A, C272359T, G290964A and A302092G). Relationship between the genotypes of 583 Hanwoo individuals by PCR-RFLP and economic traits were analyzed by general linear model. In EXT1 gene, there were four SNPs associated with economic traits such as eye muscle area breeding value, marbling score breeding value, backfat and thickness breeding value (p<0.05 to p<0.01). In conclusion, this study indicates an important role of EXT1 gene in determining the meat quality or economic characteristics in Hanwoo.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3973-3980
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• 2014

Prostate adenocarcinoma is one of the leading causes of cancer related mortality in men but still limited knowledge is available about its associated functional SNPs including rs1042522 (Pro72Arg). The present study was undertaken to explore the association of this SNP with susceptibility to prostate adenocarcinoma along with its structural and functional impacts in the Pakistani population in a case-control study. Three-dimensional structure of human TP53 with Pro72Arg polymorphism was predicted through homology modeling, refined and validated for detailed structure-based assessment. We also carried out a HuGE review of the previous available data for this polymorphism. Different genetic models were used to evaluate the genotypes association with the increased risk of PCa (Allelic contrast: OR=0.0.34, 95%CI 0.24-0.50, p=0.000; GG vs CC: OR=0.17, 95%CI 0.08-0.38, p=0.000; Homozygous: OR=0.08, 95%CI 0.04-0.15, p=0.000; GC vs CC: OR=2.14, 95%CI 1.01-4.51, p=0.046; Recessive model: OR=0.10, 95%CI 0.05-0.18, p=0.000; Log Additive: OR=3.54, 95%CI 2.13-5.89, p=0.000) except the Dominant model (OR=0.77, 95%CI 0.39-1.52, p=0.46). Structure and functional analysis revealed that the SNP in the proline rich domain is responsible for interaction with HRMT1L2 and WWOX. In conclusion, it was observed that the Arg coding G allele is highly associated with increased risk of prostate adenocarcinoma in the Pakistani population (p=0.000).