P53 Polymorphism Research Articles

Associations between the MDM2 promoter P1 polymorphism del1518 (rs3730485) and incidence of cancer of the breast, lung, colon and prostate.

The MDM2 promoter region contains several polymorphisms, some of which have been associated with MDM2 expression, cancer risk and age at cancer onset. del1518 (rs3730485) is an indel polymorphism residing in the MDM2 promoter P1 and is in almost complete linkage disequilibrium with the MDM2 promoter P2 polymorphism SNP309T>G (rs2279744). Cancer risk assessments of del1518 have previously been conducted in relatively small Chinese populations only. In this study we assessed the genotype distribution of del1518 among healthy Caucasians, African Americans and Chinese, and we estimated the Odds Ratios (OR) for incident cancer of the breast, colon, lung and prostate (n=7,081) as compared to controls (n=3,749) in a large Caucasian (Norwegian) cohort.We found the genotypes of the del1518 to vary significantly between healthy Caucasians, African-Americans and Chinese (p< 1×10−5). Further, we found a positive association of the del1518 del-allele with risk of colon cancer (dominant model: OR = 1.15; 95 % CI = 1.01 – 1.31). Stratifying according to SNP309 status, this association remained among carriers of the SNP309TG genotype (OR = 1.21; 95 % CI = 1.01 – 1.46), but with no clear association among carriers of the SNP309TT genotype. In conclusion, our findings suggest del1518 to be associated with increased risk of colon cancer.

Polymorphisms of p53 and family proteins (p63 and p73) in Thalidomide embryopathy

Polymorphisms of p53 and family proteins (p63 and p73) in Thalidomide embryopathy

The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction.

p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high-fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more-severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation.

P53 Codon 72 Polymorphism and the Risk of Cervical Cancer in Zimbabwean Women

Aims: To investigate the prevalence of p53 codon 72 polymorphism in Zimbabwean women and risk of cervical cancer Study Design: Case-control study Place and Duration of Study: Parirenyatwa Referral Hospital in Harare in between January and December 2014. Methodology: Genomic DNA from cervical cancer patients and women without cancer was extracted from whole blood and genotyping of the p53 codon 72 polymorphism was performed using the polymerase chain reaction followed by restriction fragment length polymorphism method. Results: The frequencies of the Arg/Arg; Arg/Pro and Pro/Pro genotypes in cervical cancer patients Short Research Article Kouamou et al.; IJTDH, 15(3): 1-6, 2016; Article no.IJTDH.24676 2 were reported as 15.07%, 43.84% and 41.10% respectively. An unconditional logistic regression model was used to calculate odds ratios (ORs) with a corresponding 95% confidence interval [95%CI] as measure of risk and association between the p53 polymorphism and the development of cervical cancer. The p53 Arg/Arg was found to be at increased risk for the development of cervical cancer (OR= 1.78). However its association with the development of cervical cancer was not statistically significant (p-value= 0.29; 95% CI, 0.54-6.12). Conclusion: The prevalence of the Arg/Arg genotype in our study was low in women with cervical cancer. The genotype was poorly associated with the disease.

Polymorphism of p53 in cancer prognosis.

Oncogenic activity or loss of tumour suppressor function results from genetic alterations within tumour cells, which finally leads to abnormal gene expression. TP53 gene is a well-studied tumour suppressor gene. p53 is one of the key transcription factors which regulate many cellular events, such as cell cycle, DNA damage repair, apoptosis and stress response1. Half of all human malignancies, including colon, bone, lung, breast, lymphoma, cervical, skin, gastric, ovary, brain and urological cancers, exhibit TP53 mutations, either in a single hotspot or at multiple sites, frequently accompanied by wild-type TP53 inactivation2. After p53 gene discovery, several studies have been done on how the mutational status of this gene is important in different cellular functions; the codon 72 polymorphism is one of the crucial and most studied gene alternations, which has been reported to be associated with many cancers1,2. A single nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of TP53. This polymorphism is located in a proline-rich domain, which is essential for its DNA-binding ability to induce apoptosis. The two genetic variants (Pro 72 and Arg 72) have been thought of having different functional activities. Marin et al3 have reported that some tumour-derived TP53 mutants can bind to TP73 and inactivate its biofunction. Moreover, this binding activity of TP53 mutants can be interrupted if the TP53 variants are encoded by codon 72, a common polymorphism in the human population. Generally, Arg72 might retain a less prohibitory effect to avoiding mutant TP53 binding to TP73. The TP73 gene, a TP53 homologue, can activate TP53-responsive promoters and induce apoptosis in cells deficient of TP53. The ability of mutant TP53 to bind TP73, neutralize TP73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg2. The Arg72 variant also appeared to interact more effectively with human papillomavirus (HPV)-E6 in vitro and degrade easily through the ubiquitin-proteasome pathway, resulting in inactivation of TP53 gene and induction of HPV-related tumour development2. Thomas et al4 have reported that Arg72 acts dominantly in transcriptional regulation of TP53 downstream targets that induce apoptosis or repress the transformation of primary cells. It has been shown that other than gain of function mutations, genetic polymorphism also plays crucial role in carcinogenesis. The Pro72 variant is crucial for specifically activating the TP53-dependent DNA repair genes in different cells, resulting in higher DNA-repair efficiency in vitro. Furthermore, Pro72 variant-expressed cells exhibit reduced micronuclei formation, compared with Arg72, suggesting that genomic instability is reduced in these cells2.

The 341C/T polymorphism in the GSTP1 gene and lung cancer risk: a meta-analysis.

Numerous studies have evaluated the association between the 341C/T polymorphism in glutathione S-transferase P1 (GSTP1) and lung cancer risk. However, there are conflicting results from previous studies. To derive a more precise estimation of the association, we conducted this meta-analysis. A comprehensive search was conducted to identify the eligible studies examining the GSTP1 341C/T polymorphism and lung cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The meta-analysis results showed that the GSTP1 341C/T polymorphism was significantly associated with lung cancer risk (TT vs CC: OR = 3.33, 95%CI = 1.49-7.44; CT vs CC: OR = 1.35, 95%CI = 1.10-1.65; dominant model: OR = 1.43, 95%CI = 1.05-1.96; recessive model: OR = 0.31, 95%CI = 0.14-0.70). The results indicate that the GSTP1 341C/T polymorphism may contribute to lung cancer risk. Conclusive evidence on the effects of this variant in lung cancer should be addressed in further studies.

P53 R72P Alone and in Combination with MDM2 SNP T309G is Associated with Colon Carcinoma Incidence and Survival

Introduction: Protein p53 is encoded by tumor suppressor TP53, which regulates key cellular functions such as transcription, cell cycle arrest, DNA repair and apoptosis. Murine double minute 2 homolog (MDM2), a p53 transcribed protein, negatively regulates p53. A single nucleotide polymorphism (SNP) at codon 72 of TP53 (R72P, rs rs1042522) alters an amino acid, while an SNP T309G (rs2279744) polymorphism (SNPT309G) in the promoter region of MDM2 has been reported to modulate its transcription. p53 R72P and MDM2 SNPT309G have been reported to associate alone and or in combination with various carcinomas. In this study, we aimed to determine if p53 R72P and MDM2 SNPT309G polymorphism alone or in combination are associated with colon carcinoma incidence, tumor progression and/or patient survival in Swedish population. Materials and methods: We determined polymorphisms in 151 colon carcinoma patients and 188 healthy controls by PCR-Pyrosequencing. For statistical analysis, we applied logistic regression analysis, Chi square and multivariate Cox regression to determine incidence, progression of colon carcinoma and overall patient survival respectively. Statistical analyses were two sided. Results: We found that individual carriers of Arg/Pro and Pro/Pro+Pro/Arg (Pro/--) are at 1.72 (95% CI; 1.09-2.72), and 1.659(95% CI; 1.07-2.58) fold higher risk of developing colon carcinoma compared to the carriers of Arg/Arg individuals. We did not find association of MDM2 SNPT309G with incidence of colon carcinoma. No association was found between p53 and MDM2 polymorphisms and clinicopathological parameters, except for TT variant that was correlated with low-differentiated tumors. We also found that people with Arg/Pro and Pro/--- had significantly lower overall survival compared with the people having Arg/Arg variants (Arg/Pro, OR; 1.75, 95% CI; 1.09-2.75, Pro/---, OR; 1.7, 95% CI; 1.065-2.68), but MDM2 polymorphism was not associated with patient survival. In combined analysis, with reference to Arg/Arg+TG/GG, Pro/---+TG/GG was marginally correlated with colon carcinoma incidence (OR; 1.75, 95% CI; 0.99-3.11), while Pro/---+TT was significantly correlated with poor patient survival (OR; 2.03, 95% CI; 1.029-4.02). Conclusion: p53 R72P polymorphism is associated with the incidence of colon carcinoma and patient survival. p53 and MDM2 polymorphism appear to interact with each other and modify the association with colon carcinoma incidence and patients’ survival.

Genetic polymorphisms in patients with endometriosis: an analytical study in Goiânia (Central West of Brazil).

In healthy women, intra- and extracellular controls prevent the attachment and proliferation of ectopic endometrial cells. During endometriosis, abnormalities in these control mechanisms permit the survival of endometrial cells, their subsequent attachment to the peritoneal cavity, and disease progression. These abnormal cells cause invasion of tissues and induce an inflammatory response. Several genetic, immunological, and environmental factors contribute to this complex process. In this study we examined 6 polymorphisms for 6 different genes (p53; estrogen receptor β; progesterone receptor; GSTM1; GSTT1; CYP1A1). We obtained polymorphic genotype frequencies of all genes for 50 patients and analyzed them using the Fisher exact test or G test. Initially, we analyzed the genes in groups of 2, followed by 3. We found a significant association between polymorphisms in 6 pairs of genes (p53-ERβshowed 5.9-times higher frequency in the experimental group, p53-GSTM1 showed 2.39 times higher, 65.5% patients showed p53-CYP1A1 polymorphism, ERβ-PROGINS showed 3.0-times higher frequency, while 31.25% patients showed GSTM1- PROGINS and GSTT1-CYP1A1 polymorphism). Positive results were found in 15 situations when genes were analyzed in groups of 3; the most significant result corresponded to polymorphisms of p53, ERβand GSTM1 seen in 20%; PROGINS, ERβand GSTM1 in 18%; and p53, ERβand PROGINS in 12% patients. The results indicate that the presence of polymorphisms in more than one endometriosis-related gene is associated with onset of disease and progression. Future studies should focus on these genes to understand their inter-relationships and explore the possibility of developing new diagnostic techniques based on molecular markers.

Association of mortalin (HSPA9) and other mitochondria-related genes with the risk of Parkinson's disease and Alzheimer's disease

Association of mortalin (HSPA9) and other mitochondria-related genes with the risk of Parkinson's disease and Alzheimer's disease

Association of the p53 or GSTM1 polymorphism with the risk of nasopharyngeal carcinoma: A meta-analysis.

p53 and glutathione S-transferase M1 (GSTM1) are the most popular suppressor genes. Several previous studies demonstrated positive associations of these gene polymorphisms with numerous cancer types, including hepatocellular cancer, while the association between p53/GSTM1 polymorphisms and the nasopharyngeal carcinoma (NPC) risk was inconsistent and underpowered. However, no studies investigating the combinational effect of these two genes on NPC risk were performed. To confirm the effects of p53 and GSTM1 polymorphisms on the risk of NPC, a meta-analysis of all the available previous studies associating p53 and GSTM1 with the risk of NPC was performed. A comprehensive search of PubMed, Web of Science and SD database until November 2014 was performed to identify the relevant studies. The data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. Finally, five studies with 1,419 cases and 1,707 controls were included for the p53 polymorphism and three studies with 837 cases and 1,299 controls were included for the GSTM1 polymorphism. Regarding p53, a significantly increased NPC risk was observed in the overall population (C vs. G, OR, 1.245; 95% CI, 1.045-1.483; P=0.014; additive models: CC vs. GG, OR, 1.579; 95% CI, 1.100-2.265; P=0.013 and CG vs. GG, OR, 1.230; 95% CI, 1.039-1.456; P=0.016; dominant model, OR, 1.321; 95% CI, 1.127-1.549; P=0.001; recessive model, OR, 1.429; 95% CI, 1.017-2.009; P=0.040). Concerning GSTM1, a significantly increased NPC risk was observed in the overall population (null versus non-null, OR, 1.282; 95% CI, 1.075-1.530; P=0.006). In the subgroup analyses stratified by the source of controls, a significant association of p53 with NPC risk was also demonstrated, while no association with GSTM1 was observed. Therefore, the p53 G72C polymorphism may have a susceptible role in the carcinogenesis of NPC, while genetic deletion of GSTM1 may contribute to increased susceptibility to NPC. Further large and well-designed studies are required to confirm this association.

Glutathione S-Transferase Gene Polymorphisms and Treatment Outcome in Cervical Cancer Patients under Concomitant Chemoradiation.

PurposeCisplatin based concomitant chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (CC). Glutathione S-transferase (GST), a phase II antioxidant enzyme is induced by oxidative stress generated by drugs and reactive oxidants. The present study was undertaken to evaluate the association of GSTM1, T1 and P1 polymorphisms with the outcome of CRT treatment in CC patients.MethodsA total of 227 cervical cancer patients with stages IIB-IIIB treated with the same chemoradiotherapy regimen were enrolled and genotyped for GSTM1, T1 and P1 gene polymorphisms by multiplex polymerase chain reaction (mPCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Overall survival was evaluated using Kaplan-Meier survival function and Cox proportional hazards model. All data were analyzed using SPSS (version 21.0).ResultsStratified analysis showed that GSTM1 null (M1-) genotype was associated with a significantly better survival among patients with stage IIB cervical cancer (log-rank P = 0.004) than cases with stage IIIA/IIIB. Death and recurrence were significantly higher in patients with GSTM1 present genotype (M1+) (P = 0.037 and P = 0.003 respectively) and those with M1- showed reduced hazard of death with an adjusted hazard ratio ‘HR’ of 0.47 (95% CI, 0.269–0.802, P = 0.006). Women with M1- genotype as well as in combination with GSTT1 null (T1-), GSTP1 (AG+GG) and GSTT1 null/GSTP1 (AG+GG) showed better survival and also reduced risk of death (HR = 0.31, P = 0.016; HR = 0.45, P = 0.013; HR = 0.31, P = 0.02 respectively).ConclusionsTo the best of our knowledge, this is the first study to correlate the association of GSTM1, T1 and P1 gene polymorphisms with treatment outcome of CRT treated CC patients. Our results suggested that individuals with GSTM1 null genotype and in combination with GSTT1 null and GSTP1 (AG+GG) had a survival advantage. Such genetic studies may provide prognostic information in CRT treated CC patients.

P53 codon 72 polymorphism association with head and neck squamous cell carcinoma

p53 tumoral suppressor gene harbors a functional polymorphism which codes either arginine (Arg) or proline (Pro) in the protein p53 of codon 72. Such polymorphism has been associated with the development or prognosis of head and neck squamous cell carcinoma (HNSCC).Aim: we assessed codon 72 p53 allelic frequencies and genotypes in HNSCC Iranian patients.Study design: Case Study.Materials and Methods: a total of 132 HNSCC patients and 123 healthy controls were genotyped. DNA source was from mononuclear cells of the peripheral blood. DNA amplification was done by means of the allele-specific polymerase chain reaction.Results: genotypes and allele distribution were not significantly different between patients and controls. Moreover, no statistically significant association was found between the 72 and p53 codon tumor location, gender or age at the time of diagnosis. However, the Pro/Pro genotype was significantly increase in stage IV patients (30.8%) when compared to stages I-III of the disease (11.1%) (p=0.03), and a significantly higher percentage of patients with the Pro allele had and a risk increase in stage IV disease (OR=2.2, 95% CI=1.2-4.2, p=0.01).Conclusion: data revealed that the p53 polymorphism do not impact the risk of HNSCC in Iranians, nonetheless, it can affect tumor progression to a higher tumor stage.

Abstract 51: The codon 72 polymorphism in p53 is a gain-of-function alteration leading to activation of map kinase signaling and epithelial-to-mesenchymal transition in colon cancer

Abstract Background: The codon 72 polymorphism in p53 has been implicated in several human malignancies and cancer health disparities. In this study, we determine the functional role of this frequently occurring polymorphism using an in-vitro cell based system in colon cancer. Experimental Design: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72wt), R72wt with mutation at codon 273 cysteine (R72273Cys), p53 mutation at codon 72 (P72wt) and P72wt with mutation at codon 273 (P72273Cys)] were constructed. We selected a colon cancer cell line Caco2, which does not express p53. After transfection, the expression of p53 phenotypes was confirmed by western blot analysis. Clones resistant to geneticin were assessed for cell survival; colonies were stained with 0.5% crystal violet and counted. Western blot or immunostaining analyses for proteins of MAP kinase signaling, Akt and/or epithelial mesenchymal transition mechanisms were performed to assess the gain-of-function (GOF) of P72 phenotype of p53. Results: Our study demonstrated that there was a significant increased cell survival in cells that express P72wt phenotype compared to cells that express R72wt phenotype. This cell survival was also increased in cells that express R72273Cys mutant phenotype. The P72wt phenotype induces morphological changes including cell polarization and extension of invadopodia associated with tumor progression. Western blot analyses revealed that P72wt and mutant phenotypes effectively induced the activation of p38 and extracellular signal-regulated kinase (ERK) MAP kinases. Up-regulation of phosphorylated SEK1/MKK4, or phosphorylated MEK1/2, upstream kinases of p38 MAPK, p44/42 MAPK respectively has been found to be associated with P72wt or mutant phenotypes. This activation was accompanied by up-regulation of phosphorylated-MAPKAPK-2 and phosphorylated-Hsp27, downstream targets of p38 MAPK. Furthermore, suppression of Akt activation was significantly higher in cells that express R72wt phenotype compared to cells that express P72wt or mutant phenotypes. This suppression was accompanied by down-regulation of phosphorylated glycogen synthase kinase-3β, a downstream target of p-Akt. The expression of P72wt and mutant phenotypes displayed decreased expression of E cadherin (loss of epithelial nature) and/or an increased expression of vimentin, fibrinectin (gain of mesenchymal nature). Conclusions: Collectively, these findings show that the P72 polymorphism of p53 in colon cancer is a GOF alteration leading to activation of tumor promoting phenotype. The possibility of P72 blockade may be considered in patients with colon cancer that are unresponsive to conventional treatments. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251. Citation Format: Venkat Katkoori, Lashmishankar Chaturvedi, Marc D. Basson, Upender Manne, Harvey L. Bumpers. The codon 72 polymorphism in p53 is a gain-of-function alteration leading to activation of map kinase signaling and epithelial-to-mesenchymal transition in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 51. doi:10.1158/1538-7445.AM2015-51

Abstract 4841: NF-kB - p53 gene associations and prostate cancer risk

Abstract Introduction: Prostate cancer is the most commonly diagnosed male malignancy and the second leading cause of cancer death, representing 29% of all male cancer deaths. Various tumor suppressor genes have been identified, playing a role in prostate cancer development and progression. The tumor suppressor gene p53, is the most commonly mutated gene in human cancers. Studies show that p53 can induce activation of NF-kB, and loss of NF-kB activity specifically abrogated the p53-mediated apoptotic response, without impinging on the ability to activate expression of target genes or induce cell-cycle arrest. NF-kB plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role in oncogenesis. Although it has been suggested that activation of NF-kB is not directly associated with tumor development and progression, NF-kB has been considered to be a major biomarker and therapeutic target. Enhanced NF-κB activity can be directly induced by mutations of NF-κB genes and/or oncogenes that activate the NF-κB signaling pathway. In view of the earlier reports, this study is aimed at investigating the role of p53 and NF-kB gene polymorphisms in prostate cancer risk and the possible correlation between p53-NF-kB gene in development and progression of disease. Materials &amp; methods: Blood samples were collected from 113 prostate cancer patients and a 135 normal healthy and age matched male subjects from local wellness clinics. DNA extracted from the blood at the Genetic Research Institute of the Desert is used to screen two gene polymorphisms in p53 and NF-kB using PCR-RFLP,gel electrophoresis and PCR and ABI 3130 CE-based genetic analysis. Genotype data was recorded from two methods and analyzed for frequency, Chi-Square &amp; correlations coefficients using SPSS statistical package (PASW Grad pack 18). Results: Our data showed a strong association of p53 codon248 (p&amp;lt;0.001) and NF-kB gene polymorphism (p&amp;lt;0.031) with prostate cancer. Further analysis of these two gene combinations in prostate cancer and controls showed a significant correlation (p&amp;lt;0.001) between the two gene polymorphisms in prostate cancer patients. Individually, both p53codon 248 and NF-kB del were robustly associated with prostate cancer occurrence. Moreover, the gene-gene combination predicted the occurrence of prostate cancer. Conclusions: A strong association of p53 and NF-kB gene polymorphisms with prostate cancer suggests these two genes to be possible markers for prostate cancer risk. NF-kB is known to crosstalk with many other tumor-related signaling pathways including p53. Given the unprecedented role of p53-NF-kB in tumorigenesis, p53-NF-kB risk alleles can be used as a screening device for cancer susceptibility to inform the need for more intensive ongoing cancer surveillance. Citation Format: Radhika Gade Andavolu, Catherine Stafford, Murthy Vs Andavolu, Jean-Luc Cardenas, Jacob Rubin, Ross Shore, Svetlana Rubakovic. NF-kB - p53 gene associations and prostate cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4841. doi:10.1158/1538-7445.AM2015-4841

Association of p53 and p21 polymorphisms with prostate cancer.

Cell cycle deregulation is common in human cancer. Alterations of the tumor-suppressor gene p53 and its downstream effector p21 have been indicated in the development of numerous human malignancies. Therefore, we hypothesize that the p53 codon 72 polymorphism, either on its own or in combination with p21 (C98A and C70T) polymorphisms, modifies the risk of prostate cancer within the Slovak population, and no previous studies have investigated these gene-gene interactions in the pathogenesis of prostate cancer in the Slovak population. Polymerase chain reaction-restriction fragment length polymorphism was used to determine the p53 and p21 genotypes in subjects comprising 300 prostate cancer patients and 446 healthy individuals. These 3 polymorphisms individually did not correlate with the prostate cancer risk. Conversely, the interaction between the p53 and p21 polymorphisms significantly decreased the risk of prostate cancer, with the odds ratio (OR) being 0.49 [95% confidence interval (CI), 0.27-0.86; P<0.05] for subjects carrying the p53 codon 72 arginine (Arg)/proline (Pro)+Pro/Pro and p21 C98A CA genotypes compared to the combined reference genotypes p53 codon 72 Arg/Arg and p21 C98A CC. Neither the p53 genotypes nor the p21 genotypes showed statistically significant differences in Gleason score or serum prostate-specific antigen levels (P>0.05). A decreased risk of prostate cancer association with the p21 C98A CA genotype (OR=0.58; 95% CI, 0.36-0.93; P<0.05) in non-smokers compared to the non-smokers with the p21 C98A CC genotype was observed. Smokers carrying the p53 codon 72 Pro/Pro genotype were not at any significant risk of prostate cancer (OR=2.97; 95% CI, 0.51-17.15) compared to the non-smokers with the Arg/Arg genotype. Taken together, to the best of our knowledge this is the first study to show that a combination of the variant genotypes of p53 codon 72 and p21 C98A may modify the prostate cancer risk within the Slovak population.

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

AbstractThe pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment.

Association of DNA Damage Repair Gene Polymorphisms hOGG1, XRCC1and p53 with Sickle Cell Disease Patients in India.

BackgroundOxidative stress constitutes one of the significant cause of vaso-occlusive clinical episodes in sickle cell disease (SCD) patients. It brings about the generation of reactive oxygen species and consequent damage to DNA. DNA damage repair genes such as hOGG1, XRCC1 and p53 play an important role in the repair of DNA damage during oxidative stress. However, it is not known as to the role of these genes in oxidative stress mediated vaso-occlusive clinical complications of SCD patients.ObjectiveTo see the possible association of DNA repair gene polymorphisms with clinical manifestation of SCD patients. Methods: Genotyping of DNA damage repair genes by PCR-RFLP, measurement of oxidant and anti-oxidant status, along with a clinical evaluation of 250 SCD patients and their comparison with normal individuals.ResultThe level of oxidants were high, and that of antioxidants were low in SCD patients compared to normal individuals. The prevalence of mutant alleles of hOGG1 gene, XRCC1 gene (codon 280 Arg>His) were found to be significantly higher among SCD patients as compared to controls. However, SCD patients did not show clinical association with any of these DNA repair gene polymorphisms.ConclusionThis indicates that hOGG1, p53and XRCC1 gene polymorphisms have no clinical association with SCD patients in India.

Study on p53 codon 72 polymorphism in 277 patients with breast cancer

Objective: To investigate the correlation of p53 codon 72 polymorphism with clinicopathologic features of breast cancer patients including age, tumor staging, lymph node status, receptor status of estrogen and progestin, expression of P53 protein and c-erbB-2. Methods: Blood samples were collected from 277 women with primary breast cancer. Taq-Man was used to determine the genotypes of p53 codon 72 polymorphism. Expression of ER, PR, c-erbB-2 and P53 proteins were detected with immunohistochemistry. SPSS 16.0 software was employed for statistical analysis and the relationship of p53 polymorphism with all of the clinicopathologic parameters was evaluated with χ~2 test. Furthermore, the association of p53 polymorphism with ER, PR, c-erbB-2 and P53 protein expression was analyzed by logistic regression analysis. Results: The frequency of CC, CG, and GG at p53 codon 72 was 22.0%, 51.3%, and 26.7%, respectively. No correlation was found between genotype distribution and clinicopathologic parameters of disease outcome. There was no correlation between p53 condon 72 polymorphisms and the expression of ER, PR, c-erbB-2, or P53 proteins (P0.05). P53 protein expression was associated with expression of ER, PR, and c-erbB-2 proteins (χ~2=13.492, P=0.000; χ~2=3.970, P=0.046;χ ~2= 17.956, P=0.000). Conclusion: There is no correlation between p53 codon 72 polymorphism and clinicopathologic parameters of breast cancer. P53 protein is significantly associated with ER, PR and c-erbB-2 expression. Further study using a larger sample is warranted.

MDM2 and P53 polymorphisms contribute together to the risk and survival of prostate cancer.

The p53 gene and MDM2 gene play critical roles in cell cycle arrest and apoptosis together. Here, we evaluated the associations of prostate cancer risk and survival with the joint effects of mdm2 and p53 polymorphisms. Totally 1,193 cases and 1,310 age frequency-matched controls were included in the study. Prostate cancer patients were followed to determine the intervals of overall survival and disease-free survival. The Pro72Arg Pro allele (homozygous and heterozygous) were significantly associated with prostate cancer risk with an odds ratio (OR) of 0.77 [95% confidence interval(CI), 0.64-0.93]. SNP309 T alleles were associated with a significantly decreased prostate cancer risk among Pro72Arg Pro alleles carriers (OR=0.79, 95% CI, 0.64-0.98). In addition, comparedwith the Pro72Arg Pro alleles and SNP309 G homozygous, patients carrying both SNP309 T alleles and Pro72Arg Arg homozygous had more favorable disease-free survival (hazard ratio [HR] = 0.59, 95% CI, 0.38-0.93). Our results indicated that SNP309 and Pro72Arg polymorphisms may jointly contributeto the etiology and prognosis of prostate cancer.

Association between Glutathione S-Transferase GSTM1-T1 and P1 Polymorphisms with Metabolic Syndrome in Zoroastrians in Yazd, Iran.

The aim of this study was to assess the possible association between genetic polymorphisms of the glutathione S-transferase (GST) gene family and the risk of the development of metabolic syndrome (MS) in Zoroastrian females in Yazd, Iran. In this case-control study, GSTM1, T1, and P1 polymorphisms were genotyped in 51 randomly selected MS patients and 50 randomly selected healthy controls on February 2014 among Zoroastrian females whose ages ranged from 40 to 70 yr. DNA was extracted from peripheral blood. Data were analyzed with SPSS version 17. We observed a significant association of GSTP1-I/V (Isoleucine/Valine) allele and GSTP1-V/V (Valine / Valine) allele with MS (P = 0.047 and P = 0.044, respectively). The combined analysis of the two genotypes, the present genotype of GSTT1, I/V and V/V alleles of GSTP1 genotype demonstrated a decrease in the risk of acquiring MS (OR = 0.246, P = 0.031). The null genotype of GSTM1, I/V, and V/V alleles of the GSTP1 genotype showed a lower risk in double combinations (OR = 0.15, P = 0.028 and OR = 0.13, P = 0.013, respectively). The combinations of the GSTM1 null genotypes and GSTT1 present genotypes and the GSTP1 I/V and V/V alleles together were associated with decreased risk of having MS in triple combinations (OR = 0.071, P = 0.039 and OR = 0.065, P = 0.022, respectively). GSTP1-I/V and V/V alleles, alone or in association with GSTM1 null and GSTT1 present genotypes, are related with decreased susceptibility to the development of MS in Zoroastrian females.