Association Between CYP1A1 Polymorphisms and Esophageal Cancer Susceptibility: A Case-control Study.

BACKGROUND/AIM: Environmental and genetic factors (such as polymorphisms) contribute to the development of esophageal cancer (EC), but the disease's molecular genetic markers are not fully understood. The purpose of this study was to investigate previously unstudied cytochrome P450 (CYP)1A1 polymorphisms (rs2606345, rs4646421 and rs4986883) in EC. MATERIALS AND METHODS: We performed real-time polymerase chain reaction (qPCR) to identify CYP1A1 polymorphisms (rs2606345, rs4646421, and rs4986883) in 100 patients and 100 controls. RESULTS: Smoking and tandoor fumes were significantly higher in all EC and esophageal squamous cell carcinoma (ESCC) patients compared to the control group (p<0.0001). The risk of EC was two-fold higher in hot tea drinkers compared to non-drinkers, but this factor was not significant for ESCC or esophageal adenocarcinoma (EAC) (p>0.05). The rs4986883 T>C polymorphism was not found in our population. The rs2606345 C allele was significantly associated with EC risk in men, and C-carriers who drank hot black tea had a nearly threefold higher risk of EC than non-drinkers. In addition, EC risk in hot black tea drinkers was approximately 12 times higher in rs4646421 A carriers than in non-A carriers, and approximately 17 times higher in the presence of both rs2606345 C allele and rs4646421 A allele. Furthermore, the rs2606345 AA genotype may act as a protective factor for the rs4646421 GG genotype. CONCLUSION: Among the CYP1A1 polymorphisms, rs2606345 may increase the risk of EC only in men. The risk of EC in hot tea drinkers may increase in the presence of rs4986883 and rs2606345 polymorphisms.

Association of insulin-like growth factor binding protein-7 promoter methylation with esophageal cancer in peripheral blood.

BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has an important role in many cancers, including esophageal cancer (EC). IGF-binding protein 7 (IGFBP7) is one of the proteins in this signaling pathway, and its role in cancer has not yet been fully clarified. In the present study, we evaluated the clinical relevance of IGFBP7 methylation status and mRNA expression in EC patients compared to healthy controls. We also investigated whether IGFBP7 methylation status affects mRNA expression. METHODS: The study comprised 100 EC patients and 105 healthy controls. Methylation specific PCR (MSP) was used to examine IGFBP7's promoter methylation and real-time quantitative reverse transcription PCR (qRT-PCR) was used to assess IGFBP7 mRNA expression. RESULTS: The IGFBP7 promoter methylation was significantly higher in controls than in EC patients (p < 0.05). IGFBP7 mRNA expression was significantly lower in EC patients compared to controls, especially in those over 55 years old (p < 0.0001). The globulin level and reflux were significantly higher in IGFBP7-unmethylated patients compared to IGFBP7 methylated patients (p = 0.01). In EC patients, however, there was no significant relationship between IGFBP7 mRNA expression and methylation in the peripheral blood (p = 0.33). In addition, neither IGFBP7 mRNA expression nor methylation were shown to be linked with survival (p > 0.05). CONCLUSION: Our study indicated that promoter unmethylation and mRNA expression of the IGFBP7 promoter in peripheral blood could be different biomarkers for EC. Furthermore, unmethylation of the IGFBP7 promoter in EC patients was associated with reflux and elevated globulin levels. More studies with a larger number of cases is needed to confirm this association.

CDKN1A (p21 gene) polymorphisms correlates with age in esophageal cancer.

BACKGROUND: CDKN1A gene encoding p21 is an important tumour supressor involved in the pathogenesis of cancers. A few studies have been devoted to the association between CDKN1A single nucleotide polymorphisms (SNPs) and esophageal cancer (EC) in China, India and Iran. The aim of this case-control study was to investigate the association of CDKN1A polymorphisms with EC risk in the Turkey population for the first time. METHODS: In the present study, CDKN1A SNPs (rs1801270 C > T, rs1059234 C > A and rs3176352 C > G) were genotyped with the use of TaqMan SNP genotyping assays in 102 patients and 119 controls. RESULTS: The genotypes and alleles of CDKN1A SNPs were not significantly different among patients and controls. However, TT-genotype and T-allele of the rs1059234, the rs1801270 CC-genotype and rs3176352 G-allele were significantly associated with EC risk for ≤ 55 age (p < 0.05). In those over 55 age, CC-genotype and C-allele of the rs1059234 was significantly associated with EC (p < 0.05). The rs1059234 T-carriers had a higher risk of high globulin level (p = 0.017) and low albumin/globulin ratio (p = 0.019) when compared to non-T carriers (CC). The rs3176352 CC-genotype carriers had a higher risk of esophageal adenocarcinoma (EAC) subtype when compared to CG-genotype carriers and CG-genotype carriers had a higher risk of squamous cell carcinoma (ESCC) subtype (OR/95% CI = 4.00/1.06-15.08, p = 0.04). The rs3176352 CC-genotype is also a risk factor for the higher BMI (p = 0.04) and the higher CA-19-9 level (p = 0.009). CONCLUSION: Our study suggests that the CDKN1A polymorphisms may play an important role in EC risk in relation to age. Future studies are needed to validate our findings.

Antiproliferative and Apoptotic Role of Novel Synthesized Cu(II) Complex with 3-(3-(4-fluorophenyl)Triaz-1-en-1-yl) Benzenesulfonamide in Common Cancer Models.

BACKGROUND/AIM: Chemotherapeutic treatment options are often ineffective due to the development of resistance in cancer cells. Therefore, developing new anti-cancer agents is crucial for cancer treatment. Some triazine derivatives, their complexes and Copper(II) have anti-cancer effects on cancer cells. In this study, we aimed to determine the anti-proliferative effect of the novel synthesized Cu(II) complex with 3-(3-(4-fluorophenyl)triaz-1-en-1-yl) benzene-sulfonamide compound on the common cancer cell lines HeLa, MDA-MB-231, A2780 and MCF7. MATERIALS AND METHODS: Common cancers cell lines were treated with copper complexes. Cell viability and apoptotic gene expression were examined. RESULTS: Novel synthesized copper complex led to decreased viability of all cell lines. It also induced apoptosis via increasing the expression of caspase-3, caspase-9, Bax and p53 proteins and decreasing ERK expression. CONCLUSION: The novel synthesized copper complex has a significant inhibitory effect on the viability of cancer cell lines and can be considered as an antitumor agent for further studies.

Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women.

BACKGROUND: Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL. METHODS: Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. RESULTS: Telomeres were shorter in tumor tissues compared to controls (P<.0001). The mean TL was higher in breast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters. CONCLUSION: These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association.

Investigation of the association between mitochondrial DNA and p53 gene mutations in transitional cell carcinoma of the bladder.

Bladder carcinoma is the most common malignancy of the urinary tract. The major aim of the present study is to investigate the association between mitochondrial DNA (mtDNA) and p53 gene mutations in bladder carcinoma. A total of 30 patients with transitional cell carcinoma and 27 controls were recruited for the study. Bladder cancer tissues were obtained by radical cystectomy or transurethral resection. Genomic DNA was extracted from peripheral blood. mtDNA and p53 genes were amplified by polymerase chain reaction and sequenced directly. A total of 37 polymorphisms were identified, among which, 2 mutations were significant in the patient group, and 1 mutation was significant in the control group. Additionally, 5 different moderate positive correlations between mtDNA mutations and 3 different positive correlations between p53 gene and mtDNA mutations were detected. The high incidence of mtDNA and p53 gene mutations in bladder cancer suggests that these genes could be important in carcinogenesis.

Correlation between the DNA methylation and gene expression of IGFBP5 in breast cancer.

BACKGROUND: The insulin-like growth factor binding protein5 (IGFBP5) is often dysregulated in human cancers and considered neither a tumor suppressor nor an oncogene. OBJECTIVE: We aim to examine the reason of the changeable gene regulation of IGFBP5 in the case of methylation in breast cancer. METHODS: We used methyl-specific polymerase (MSP) chain reaction to detect CpG methylation of IGFBP5 promoter and exon-I in breast cancer and adjacent tissues. Gene expression is evaluated by quantative polymerase chain reaction (qPCR). RESULTS: IGFBP5 methylation was detected in 24 of 58 (41%) and 54 of 56 (96.5%) promoter and exon-I site respectively in tumor tissues. In adjacent tissues 17 of 58 (29%) and 53 of 56 (96.5%) was methylated. IGFBP5 expression was higher estrogene receptor (ER)(+) than ER(-) patients (p = 0.0549). Beside, we found a positive correlation between the expression of IGFBP5 and G2 tumor grade (p = 0.0131). However, no correlation was observed between IGFBP5 expression and age, menopause or the presence of lymph node metastasis (p > 0.05). CONCLUSIONS: In summary, our results showed that IGFBP5 promoter and exon-I methylation did not have any differences between tumor and adjacent tissues so that IGFBP5 methylation did not change IGFBP5 gene regulation in breast cancer. This is the first study investigating the IGFBP5 gene methylation in breast cancer.

Detection of PIK3CA gene mutations with HRM analysis and association with IGFBP-5 expression levels in breast cancer.

Breast cancer is the second most common cancer and second leading cause of cancer deaths in women. Phosphatidylinositol-3-kinase (PI3K)/AKT pathway mutations are associated with cancer and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations have been observed in 25-45% of breast cancer samples. Insulin growth factor binding protein-5 (IGFBP-5) can show different effects on apoptosis, cell motility and survival in breast cancer. We here aimed to determine the association between PIK3CA gene mutations and IGFBP-5 expressions for the first time in breast cancer patients. Frozen tumor samples from 101 Turkish breast cancer patients were analyzed with high resolution melting (HRM) for PIK3CA mutations (exon 9 and exon 20) and 37 HRM positive tumor samples were analyzed by DNA sequencing, mutations being found in 31. PIK3CA exon 9 mutations (Q546R, E542Q, E545K, E542K and E545D) were found in 10 tumor samples, exon 20 mutations (H1047L, H1047R, T1025T and G1049R) in 21, where only 1 tumor sample had two exon 20 mutations (T1025T and H1047R). Moreover, we detected one sample with both exon 9 (E542Q) and exon 20 (H1047R) mutations. 35% of the tumor samples with high IGFBP-5 mRNA expression and 29.4% of the tumor samples with low IGFBP-5 mRNA expression had PIK3CA mutations (p=0.9924). This is the first study of PIK3CA mutation screening results in Turkish breast cancer population using HRM analysis. This approach appears to be a very effective and reliable screening method for the PIK3CA exon 9 and 20 mutation detection. Further analysis with a greater number of samples is needed to clarify association between PIK3CA gene mutations and IGFBP-5 mRNA expression, and also clinical outcome in breast cancer patients.