Ebid, Gamal T.
(Clinical Pathology Department, National Cancer Institute, Cairo University)
,
Sedhom, Iman A.
(Pediatric Oncology Department, National Cancer Institute, Cairo University)
,
El-Gammal, Mosaad M.
(Medical Oncolog Departement, National Cancer Institute, Cairo University)
,
Moneer, Manar M.
(Medical Biostatistic Departement, National Cancer Institute, Cairo University)
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...
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.
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.
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문제 정의
Results from this study suggested that dietary habits in this popmental agents, and the prevalent consanguinity in Cambodia justify further research, which will advance our understanding of the risk factors for the disease in young adults. These studies should investigate environmental exposures, family history, and consanguinity as well as explore gene–environment interactions in colorectal cancer carcinogenesis in this high-risk population.
제안 방법
To the best of our knowledge, no previous studies investigated the possible role of these three gene polymorphisms and their gene-gene interaction in the pathogenesis of AML. In this work, we investigated the frequency of P53, P21, and MDM2 polymorphisms among AML patients referring to the National Cancer Institute (NCI) and in apparently normal healthy controls, aiming to describe the prevalence of such polymorphisms and detect whether or not they have implications for pathogenesis.
The MDM2 T309G polymorphism was determined Each PCR assay was performed using 100 ng of genomic DNA, 0.2 μM of each primer, 1 U of Hot Start Taq DNA polymerase (Quiagen), 200 μM dNTP, 1.5 mM MgCl2, 10 mM Tris-HCl (pH 8.4), and 50 mM KCl.
대상 데이터
Diagnosis was performed according to clinical, morphological, cytochemical and immunophentypic examination. In addition, 72 apparently healthy individuals were included in the study as a control group. Informed written consent was obtained from all participants involved in the study or from their parents and approval of the IRB, NCI, Cairo University was obtained.
3 years. The patient group included 43 males (55.8%) and 34 females (44.2%).
This study was carried out on 77 newly diagnosed AML patients who presented to the Medical and Pediatric Oncology Departments, NCI, Cairo University. Diagnosis was performed according to clinical, morphological, cytochemical and immunophentypic examination.
데이터처리
For quantitative data, comparison between two groups was done using Mann-Whitney test (non-parametric t-test). Comparison between 3 groups was done using Kruskal-Wallis test (non-parametric ANOVA). Logistic regression was used for calculation of odds ratio (OR) with 95% confidence interval (CI) for risk estimation.
Chi-square test (Fisher’s exact test) was used to examine the relation between qualitative variables. For quantitative data, comparison between two groups was done using Mann-Whitney test (non-parametric t-test). Comparison between 3 groups was done using Kruskal-Wallis test (non-parametric ANOVA).
이론/모형
Chi-square test (Fisher’s exact test) was used to examine the relation between qualitative variables.
, 1988). Genotyping for all studied loci was performed by PCR-RFLP method. Primers sequences, restriction enzymes and fragments obtained are presented in Table 1.
성능/효과
In conclusion, this is the first report to the best of our knowledge to show the relation between AML and three single nucleotide polymorphisms in the P53 pathway. There is a significant association between P21 polymorphism and AML and MDM2 polymorphic allele increases this association.
(2008) who tested associations between 171 patients with t-AML and 2 common functional P53-pathway variants, the MDM2 SNP309 and the TP53 codon 72 polymorphism. They showed that MDM2 SNP309G allele was associated with a modest increased risk in de novo AML but not in therapy-related AML. So far there exists one published leukemia study claiming that the MDM2 SNP309 G allele reduced the risk of the disease in a Singaporean Chinese population (Phang et al.
2%). We found that P21 (ser/arg) heterozygous showed a statistical significant difference among AML patients compared to controls (p=0.017, OR 2.946, 95% CI 1.216-7.134), also P21 polymorphism (ser/arg plus arg/arg) versus P21 wild type was higher in AML patients compared to controls (p=0.008). Figure 2 demonstrates the different PCR/RFLP p21 fragments.
후속연구
78%) is approximately 4 times hicohort. Results from this study suggested that dietary habits in this popmental agents, and the prevalent consanguinity in Cambodia justify further research, which will advance our understanding of the risk factors for the disease in young adults. These studies should investigate environmental exposures, family history, and consanguinity as well as explore gene–environment interactions in colorectal cancer carcinogenesis in this high-risk population.
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