Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients

Introduction: TP53 gene is the most frequently altered tumor suppressor gene in breast cancer. It has been observed that MDM2 plays a central role in regulating the TP53 pathway. This study aimed to investigate the role of TP53 Arg72Pro and MDM2 T309G polymorphisms in breast cancer patients. Material and method: The TP53 (Arg72Pro) and MDM2 (T309G) polymorphisms were studied in a hospital-based case control study by AS-PCR in 100 breast cancer patients and 100 healthy control subjects. Results: It was observed that TP53 Arg72Pro polymorphism was significantly associated with breast cancer (v2 = 9.92, p = 0.007). A significantly increased breast cancer risk was associated with the Proline allele [odds ratio 1.84 (95 % CI: 1.22-2.77), risk ratio 1.34 (95 % CI: 1.11-1.63), p value 0.003], HER2/neu status (p = 0.01) and distant metastasis (p = 0.05). On the other hand, we have found a significant correlation between MDM2 (T309G) polymorphism with HER2/neu status (v2 = 11.14, p = 0.003) and distant metastasis (p value = 0.04). Conclusion: Our finding suggests that TP53 (Arg72Pro) polymorphism may play a significant role as risk factor for breast cancer in north Indian breast cancer patients. While MDM2 (T309G) polymorphism may not be directly associated with the risk of breast cancer occurrence in the same population, but it may play role in disease progression by triggering TP53 (AU)

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Potential impact of (rs 4645878) BAX promoter -248G > A and (rs 1042522) TP53 72Arg > pro polymorphisms on epithelial ovarian cancer patients

Background. In India, Epithelial ovarian cancer has emerged as one of the most common malignancies affecting women. Tumor protein 53 (TP53) induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter. Therefore, we hypothesized that single-nucleotide polymorphism of BAX promoter −248G>A and TP53 72Arg>Pro gene may jointly contribute to ovarian cancer risk. Objectives. This study aimed at exploring the association of BAX promoter −248G>A and TP53 72Arg>Pro gene polymorphism with risk of developing EOC and its clinicopathological features and to evaluate gene-gene interaction of these two polymorphisms with risk of developing EOC. Materials. The study was conducted on 70 Epithelial ovarian cancer patients and 70 healthy controls. Genotyping of p53 codon 72 and BAX promoter gene was examined by ASO-PCR and PICA-PCR, respectively. Odds ratios and 95 % confidence intervals were calculated. Results. We found an increased cancer risk associated with the BAX AA (ORs = 4.1, 95 %, CI = 1.23-13.97) genotype. An increased risk was also associated with the TP53 Pro/Pro (OR = 4.4, 95 % CI = 1.40-13.99) and Arg/Pro genotype (OR = 2.3, 95 % CI = 1.13-4.86). The gene-gene interaction of these polymorphisms increased EOC risk in a more than additive manner (ORs for the presence of both BAX AA and TP53 Arg/Pro genotypes = 8.7, 95 % CI = 1.66-45.48). BAX GG genotype was associated with adverse staging of cancer (P = 0.01). Conclusions. The findings suggest that polymorphism of BAX and TP53 genes may be potential genetic modifiers for developing ovarian cancer (AU)

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Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features

Background. MicroRNAs (miRs) have been implicated in the etiology of various human cancers. The aim of this study was to investigate the association of the expression of three members - miR 200a, miR 200b, and miR 200c belonging to the miR-200 family with clinicopathological characteristics and their impact on the progression of epithelial ovarian cancer (EOC). Materials and methods. Total RNA from serum was isolated by Trizol method, polyadenylated, and reverse transcribed into cDNA. Expression levels of miR-200a, miR-200b, and miR-200c were detected by using miRNA qRT-PCR. We measured miR expression in 70 serum samples of EOC patients with matched controls using U6 snRNA as a reference. Levels of miR expression was compared with distinct clinicopathological features. Results. Expression of miR-200a was found to be greater than six-fold (p = 0.01), miR-200b and miR-200c greater than three-fold (p = 0.01) in comparison with matched normal controls. Association of miRNA expression with clinicopathological factors and progression was statistically evaluated. The expression levels of miR-200a and miR-200c were found to be significantly associated with disease progression (p = 0.04 and p < 0.001, respectively). miR-200a overexpression was found be associated with tumor histology and stage. Patients with lymph node metastasis showed significant elevation of miR-200c (p = 0.006). The AUC in ROC curve also indicated that serum levels of miR-200a and miR-200c might be worthwhile as a diagnostic tool in the near future. Conclusion. Our findings suggest that miR-200a, miR-200b, and miR-200c overexpressions are associated with the aggressive tumor progression and be recognized as reliable markers to predict the prognosis and survival in EOC patients (AU)

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Does vitamin D mediate inhibition of epithelial ovarian cancer by modulating cytokines?

Objective. Vitamin D deficiency is reported to be involved in pathogenesis of ovarian cancer. But the mechanism is yet to be explored. An imbalance between Th1 and Th2 activity play a crucial role in pathogenesis of many cancers. The purpose of the study is to find out the Th1/Th2 status by estimating TNF-α (Th1 marker) and IL-4 (Th2 marker) in ovarian cancer cases and controls and to correlate these with serum vitamin D levels. Materials and methods. A case–control study with 50 ovarian cancer cases and 50 healthy controls was conducted. The cytokines TNF-α and IL-4 were estimated by ELISA. Serum vitamin D was measured by electro-chemiluminescence immunoassay method. Results. Median TNF-α levels (12.2 vs 6.2 pg/ml; p value <0.001) were significantly higher in ovarian cancer patients and mean IL-4 levels (2.22 ± 0.51 vs 2.99 ± 0.68 pg/ml; p value <0.05) were significantly lower as compared to those of controls. Levels of TNF-α and IL-4 did not vary significantly with clinical staging, and histological grading. Vitamin D levels were negatively correlated with TNF-α and positively correlated with IL-4. Conclusions. Low vitamin D levels promotes Th1 activity increasing TNF-α levels and inhibits Th2 activity decreasing IL-4 levels in ovarian cancer. These low levels of vitamin D may induce pro-inflammatory micro ambience which might contribute to pathogenesis of ovarian cancer (AU)

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CC genotype of anti-apoptotic gene BCL-2 (-938 C/A) is an independent prognostic marker of unfavorable clinical outcome in patients with non-small-cell lung cancer

Background: B cell lymphoma 2 (BCL-2) gene is a well-known regulator of apoptosis and a key element in cancer development and progression. A regulatory (−938C>A, rs2279115) single-nucleotide polymorphism in the inhibitory P2 BCL-2 gene promoter generates significantly different BCL-2 promoter activities and has been associated with different clinical outcomes in various malignancies. The aim of the present study was to analyze the possible influence of the (−938C>A) SNP on the risk and survival of Indian patients suffering from NSCLC. Materials and methods: A hospital-based case–control study of 155 age- and sex-matched patients diagnosed with NSCLC and 155 cancer-free controls was conducted and genotyped by performing PIRA–PCR to elucidate the putative association between clinical outcome and genotypes of BCL-2 (−938C>A, rs2279115). The association of the polymorphism with the survival of NSCLC patients was analyzed by Kaplan–Meier curves. Results: In Indian NSCLC, patients increased risk of developing NSCLC was found to be associated with BCL-2 (−938) CC genotype, [OR 3.68 (1.92−6.79), RR 1.87 (1.35−2.57) and RD 31.03 (16.79−45.27) p 0.00006 for CC and OR 2.08 (1.18−3.66), RR 1.36 (1.08−1.71) and RD 17.74 (4.68−30.81) p 0.01 for AC genotype]. Patients homozygous for C allele exhibited a significant poor overall survival compared with patients displaying AC + CC or AC or AA genotype [median survival (months) 8 vs. 11 vs. 14 vs. 35.5 (p < 0.0001)]. In addition, significant associations were observed between TNM stage, histological type, distant metastases status, family history of any cancer, gender and age group of NSCLC patients with BCL-2 (−938C>A) polymorphism. Conclusion: Genetic polymorphism in the inhibitory P2 promoter region of anti-apoptotic BCL-2 genes contributes to the risk of developing non-small-cell lung cancer in Indian population. BCL-2 (−938CC) genotype was an independent adverse prognostic factor for patients with NSCLC (AU)

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