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    Association between ABCB1 (MDR1) Gene 3435 C>T Polymorphism and Colchicine Unresponsiveness of FMF Patients
    (Taylor & Francis Ltd, 2011) Ozen, Filiz; Silan, Coskun; Uludag, Ahmet; Candan, Ferhan; Silan, Fatma; Ozdemir, Semra; Atik, Sinem
    The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.
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    Combined Germline Variations of Thrombophilic Genes Promote Genesis of Lung Cancer
    (Asian Pacific Organization Cancer Prevention, 2013) Ozen, Filiz; Polat, Fikriye; Arslan, Sulhattin; Ozdemir, Ozturk
    Background: A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas. Materials and Methods: A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared. Results: Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers. Conclusions: The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.
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    Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G Variations in Breast Carcinoma
    (Asian Pacific Organization Cancer Prevention, 2013) Ozen, Filiz; Erdis, Eda; Sik, Ebru; Silan, Fatma; Uludag, Ahmet; Ozdemir, Ozturk
    Background: Various oncogenes related to cancer have been extensively studied and several polymorphisms have been found to be associated with breast cancer. The current report outlines analysis of germ-line polymorphisms for C677T, A1298C (MTHFR), Leiden, R2 (FV) and 5G/4G (PAI-1) in Turkish breast cancer patients. We studied 51 cases diagnosed with invasive ductal and operable with lymph node-positive breast cancer and 106 women as a control group. Materials and Methods: Peripheric blood-DNA samples were used for genotyping by StripAssay technique which is based on the reverse-hybridization principle and real-time PCR methods and results were compared statistically. Results: The frequency of the MTHFR gene 677T and 1298A alleles were significantly higher in cancer patients than in the healthy subjects. The T allele frequency in codon 677 was 2.3-fold and C allele frequency was 3.1-fold increased in BC when compared to the control group for the MTHFR gene. Both differences were statistically significant (OR: 2.295, CI: 1.283-4.106), p<0.006 and (OR: 3.131, CI: 1.826-5.369), p<0.0001 respectively. The R2 allele frequency of FV gene was 5.1-fold increased in the current BC when compared to the control group and that difference was also statistically significant (OR: 5.133, CI: 1.299-20.28), p<0.02. Conclusions: The present data suggest that germ-line polymorphisms of C677T, C1298A for MTHFR and R2 for FV are associated in breast cancer and may be additional prognostic markers related to breast cancer survival. The results now need to be confirmed in a larger group of patients.
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    Methylenetetrahydrofolate Reductase Gene Germ-Line C677T and A1298C SNPs are Associated with Colorectal Cancer Risk in the Turkish Population
    (Asian Pacific Organization Cancer Prevention, 2014) Ozen, Filiz; Sen, Metin; Ozdemir, Ozturk
    Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse-hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group. The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size.
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    Recurrent Pregnancy Loss and Its Relation to Combined Parental Thrombophilic Gene Mutations
    (Mary Ann Liebert, Inc, 2012) Ozdemir, Ozturk; Yenicesu, Gonca Imir; Silan, Fatma; Koksal, Binnur; Atik, Sinem; Ozen, Filiz; Gol, Mert
    Background and Aim: Recurrent pregnancy loss (RPL) is a heterogeneous disorder that has been associated with antiphospholipid syndrome and other prothrombotic parameters. We aimed to investigate the prevalence of 12 thrombophilic gene mutations in RPL couples in the current results. Method: In a total of 543 Turkish women with RPL and 327 of their male partners (870 individuals with RPL), and a control group of 106 fertile couples (control) were analyzed for factor V leiden (FVL), factor V H1299R, factor II prothrombin G20210A, FXIII V34L, b-fibrinogen -455G>A, plasminogen activator inhibitor-1 (PAI-1), GPIIIa L33P (HPA-1 a/b L33P), methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q, and Apo E genes. Results: The overall, heterozygous and/or homozygous point mutations in FVL -FVR2, ApoE2, PAI-1, MTHFR C677T - A1298C, and ACE genes were associated with RPL. There was no meaningful association between RPL and other studied genes. Conclusion: The homozygosity of 4G in PAI-1 and MTHFR C677T genes in women with RPL, and heterozygosity of FVL, FVR2, ACE, and ApoE2 genes in both parents play crucial role in RPL and should be considered as a risk factor in RPL. Current results showed that RPL is related to combined parental (not only maternal) thrombophilic gene mutations.
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    The CYP4502D6*4 and*6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients
    (Springer France, 2016) Yalcintepe, Sinem; Ozdemir, Ozturk; Silan, Coskun; Ozen, Filiz; Uludag, Ahmet; Candan, Ferhan; Silan, Fatma
    The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex PCR-based reverse-hybridization StripAssay and real-time PCR methods. DNA banks isolated from blood-EDTA were retrospectively used in the current patients and results were compared statistically. Increased CYP2D6 *4 and *6 allele frequencies were highly detected in the colchicine non-responsive FMF patients when compared to the responsive group. Results showed the frequencies of major CYP2D6 *1(wild), *3(2637A > delA), *4(G1934A), *5(total gene deletion) and *6(1707T del) alleles in 0.550, 0.042, 0.158, 0.025 and 0.225 for non-responder and 0.880 and 0.120 (CYP2D6*1 and *4) for the responder groups, respectively. Despite small sample size, this study suggests that there is an association between CYP2D6*4 and CYP2D6*6 alleles and drug intoxicants in colchicine non-responder FMF patients.
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    The Proto-Oncogene KRAS and BRAF Profiles and Some Clinical Characteristics in Colorectal Cancer in the Turkish Population
    (Mary Ann Liebert Inc, 2013) Ozen, Filiz; Ozdemir, Semra; Zemheri, Ebru; Hacimuto, Gizem; Silan, Fatma; Ozdemir, Ozturk
    Objectives: The aim of the current study was to investigate the prevalence and predictive significance of the KRAS and BRAF mutations in Turkish patients with colorectal cancer (CRC). Methods: Totally, 53 fresh tumoral tissue specimens were investigated in patients with CRC. All specimens were obtained during routine surgery of patients who were histopathologically diagnosed and genotyped for common KRAS and BRAF point mutations. After DNA extraction, the target mutations were analyzed using the AutoGenomics INFINITI (R) assay, and some samples were confirmed by quantitative real-time polymerase chain reaction fluorescence melting curve analyses. Results: KRAS mutations were found in 26 (49.05%) CRC samples. Twenty-seven samples (50.95%) had wild-type profiles for KRAS codon 12, 13, and 61 in the current cohort. In 17 (65.38%) samples, codon 12; in 7 (26.93%) samples, codon 13; and in 2 (7.69%) samples, codon 61 were found to be mutated, particularly in grade 2 of tumoral tissues. No point mutation was detected in BRAF codon Val600Glu for the studied CRC patients. Conclusions: Our study, based on a representative collection of human CRC tumors, indicates that KRAS gene mutations were detected in 49.05% of the samples, and the most frequent mutation was in the G12D codon. Results also showed that codons 12 and 13 of KRAS are relatively frequently without BRAF mutation in a CRC cohort from the Turkish population.