Browsing by Author "Özçelik, T."

Now showing 1 - 20 of 29

Open Access
2012 William allan award introduction: Uta Francke
(Elsevier, 2013-03-07) Özçelik, T.
Open Access
Analysis of MYH Tyr165Cys and Gly382Asp variants in childhood leukemias
(Springer, 2003) Akyerli, C. B.; Özbek, U.; Aydin-Sayitoǧlu, M.; Sirma, S.; Özçelik, T.
[No abstract available]
Open Access
Circulating endothelial progenitor cells in multiple myeloma: implications and significance
(American Society of Hematology, 2005) Zhang, H.; Vakil, V.; Braunstein, M.; Smith, E. L. P.; Maroney, J.; Chen, L.; Dai, K.; Berenson, J. R.; Hussain, M. M.; Klueppelberg, U.; Norin, A. J.; Akman, H. O.; Özçelik, T.; Batuman, O. A.
Angiogenesis governs the progression of multiple myeloma (MM). Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease activity and therapeutic response in 31 consecutive patients with MM. CECs, identified as CD34+/CD146+/CD105+/CD11b- cells, were 6-fold higher in patients compared to controls and correlated positively with serum M protein and β2-microglobulin. Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on matrigel; these processes were inhibited after effective thalidomide treatment. Co-expression of vascular endothelial growth factor receptor-2 (KDR) and CD133 characterized EPCs in MM, and KDR mRNA elevations correlated with M protein levels. In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-β and thrombin. Thus, elevated levels of CECs and EPCs covary with disease activity and response to thalidomide, underscoring the angiogenic aspect of MM and suggesting that angioblastlike EPCs are a pathogenic biomarker and a rational treatment target in MM. The results also highlight the anti-angiogenic properties of thalidomide and CC-5013 and further elucidate possible mechanisms of their effectiveness against MM.
Open Access
Coagulation factor V gene mutation increases the risk of venous thrombosis in Behcet's disease
(Oxford University Press, 1996) Gül, A.; Özbek, U.; Öztürk, C.; Inanç, M.; Koniçe, M.; Özçelik, T.
We investigated the prevalence of the coagulation factor V gene G1691A mutation in 64 patients with Behcet's disease (BD) and in 107 apparently healthy individuals. The mutation was present in the heterozygous state in 37.5% of the patients with a history of deep vein thrombosis (12/32) and in 9.4% of the patients without any thrombotic event (3/32). Eleven healthy individuals were also heterozygous for the mutation (10.3%). The prevalence of the mutation in BD patients with and without thrombosis was significantly different (P = 0.0079). We conclude that the factor V gene mutation may play a major role in the development of venous thrombosis in BD.
Open Access
DNA repair gene polymorphisms and bladder cancer susceptibility in a Turkish population
(International Institute of Anticancer Research, 2006) Karahalil, B.; Kocabas, N. A.; Özçelik, T.
Background: Occupational exposure and life style preferences, such as smoking are the main known environmental susceptibility factors for bladder cancer. A growing list of chemicals has been shown to induce oxidative DNA damage. Base excision repair (BER) genes (X-ray repair cross complementing 1, XRCC1 and human 8-oxoguanine DNA glycosylase 1, OGG1) may play a key role in maintaining genome integrity and preventing cancer development. Materials and Methods: We tested whether polymorphisms in XRCC1 and OGG1 are associated with bladder cancer risk by using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay. In addition, the possible modifying affect of cigarette smoking was evaluated. Results: No studies, to date, have examined the association between genetic polymorphisms in DNA repair genes and bladder cancer susceptibility, in the Turkish population. We found the OGG1 Cys326Cys genotype to be more frequent among bladder cancer patients (odds ratio (OR): 2.41 (95% CI, 1.36-4.25)). However, in the case of XRCC1, there was no significant difference in susceptibility to bladder cancer development between patients with the Arg399 and these with the Gln399 allele (OR: 0.72 (95% CI, 0.41-1.26)). Conclusion: Our data showed that OGG1 genetic polymorphisms might be useful as prognostic genetic markers for bladder cancer in the clinical setting.
Open Access
Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair
(B M J Group, 2014) Dal, G. M.; Ergüner, B.; Saǧıroǧlu, M. S.; Yüksel, B.; Onat, O. E.; Alkan C.; Özçelik, T.
Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 for twin II. Conclusions: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.
Open Access
Echinococcus against cancer: why not?
(John Wiley & Sons, Inc., 2003) Akgül, H.; Tez, M.; Ünal, A. E.; Keşkek, M.; Sayek, İ.; Özçelik, T.
Open Access
Endothelial progenitor cells display clonal restriction in multiple myeloma
(BioMed Central Ltd., 2006) Braunstein, M.; Özçelik, T.; Baǧişlar, S.; Vakil, V.; Smith, E. L. P.; Dai, K.; Akyerli, C. B.; Batuman O. A.
Background: In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. Methods: A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (VH). Results: In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with VH primers resulted in amplification of the same product in EPCs and bone marrow cells in 71 % (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI. Conclusion: Our results suggest that EPCs in at least a substantial subpopulation of MM patients are related to the neoplastic clone and that this is an important mechanism for upregulation of tumor neovascularization in MM. © 2006 Braunstein et al; licensee BioMed Central Ltd.
Open Access
The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographicaly diverse populations
(Cell Press, 2000) Mazoyer, S.; Leary, J.; Kirk, J.; Fleischmann, E.; Wagner, T.; Claes, K.; Messiaen, L.; Foulkes, W.; Desrochers, M.; Simard, J.; Phelan, C. M.; Kwan, E.; Narod, S. A.; Vahteristo, P.; Nevanlinna, H.; Durando, X.; Bignon, Y. J.; Peyrat, J. P.; Bonnardel, C.; Sinilnikova, O. M.; Puget, N.; Lenoir, G. M.; Audoynaud, C.; Goldgar, D.; Maugard, C.; Caux, V.; Gad, S.; Stoppa-Lyonnet, D.; Noguès, C.; Lidereau, R.; Machavoine, C.; Bressac-De Paillerets, B.; Kuschel, B.; Betz, B.; Niederacher, D.; Beckmann, M. W.; Hamann, U.; Ponder, B. A. P.; Robinson, M.; Taylor G. R.; Bishop, T.; Catteau, A.; Solomon, E.; Cohen, B.; Steel, M.; Collins, N.; Stratton, M.; Van Der Looij, M.; Oláh, E.; Miller, N. J.; Barton, D. E.; Sverdlov, R. S.; Friedman, E.; Radice P.; Montagna, M.; Sensi, E.; Caligo, M.; Van Eijk, R.; Devilee, P.; Van Der Luijt, R.; Heimdal, K.; Møller, P.; Borg, Å.; Diez, O.; Cortes, J.; Domenech, M.; Baiget, M.; Osorio, A.; Benítez, J.; Maillet, P.; Sappino, A. P.; Özdag, H.; Özçelik, T.; Ozturk, M.; Rohlfs, E. M.; Boyd, J.; McDermott, D.; Offit, K.; Unger, M.; Nathanson, K.; Weber, B. L.; Sellers, T. A.; Hampton, E.; Couch, F. J.; Neuhausen, S.; Gayther, S. A.
Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report.
Open Access
Expression of IFITM1 in chronic myeloid leukemia patients
(Elsevier, 2005) Akyerli, C. B.; Beksac, M.; Holko, M.; Frevel, M.; Dalva, K.; Özbek, U.; Soydan, E.; Özcan, M.; Özet, G.; İlhan, O.; Gürman, G.; Akan, H.; Williams, B. R. G.; Özçelik, T.
We investigated the peripheral blood gene expression profile of interferon induced transmembrane protein 1 (IFITM1) in sixty chronic myeloid leukemia (CML) patients classified according to new prognostic score (NPS). IFITM1 is a component of a multimeric complex involved in the trunsduction of antiproliferative and cell adhesion signals. Expression level of IFITM1 was found significantly different between the high- and low-risk groups (P = 9.7976 × 10-11) by real-time reverse transcription polymerase chain reaction (RT-PCR). Higher IFITM1 expression correlated with improved survival (P = 0.01). These results indicate that IFITM1 expression profiling could be used for molecular classification of CML, which may also predict survival.
Open Access
Genomic landscape of the Greater Middle East
(Nature Publishing Group, 2016-09) Özçelik, T.; Onat, O. E.
Study of the Greater Middle East (GME), home to approximately 10% of the world's population, has made invaluable contributions to the characterization of rare genetic disease, especially recessive conditions arising from the tradition of consanguinity and large families with multiple children. A new study now reports 1,111 unrelated exomes from the GME and provides a comprehensive view of genetic variation for enhanced discovery of disease-associated genes.
Open Access
Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients
(Elsevier, 2000-10) Özdag, H.; Tez, M.; Sayek, I.; Müslümanoglu, M.; Tarcan, O.; Içli, F.; Öztürk, M.; Özçelik, T.
Germ line BRCA1 and/or BRCA2 mutations were screened in 50 Turkish breast and/or ovarian cancer patients composed of hereditary, familial, early onset and male cancer groups. Genomic DNA samples were tested by heteroduplex analysis and DNA sequencing. Two truncating BRCA2 mutations, one novel (6880 insG) and one previously reported (3034 delAAAC), were found in two out of six (33%) hereditary breast and/or ovarian cancer patients. A novel truncating (1200 insA) and a missense (2080A→G) BRCA1 mutation was found in two of 27 (7%) individuals in the early onset group. A total of four (8%) disease-causing mutations in 50 breast cancer patients were identified in BRCA1 and BRCA2 genes. In addition, five BRCA1 sequence variants have been identified in 23 patients. These results indicate that BRCA1 and BRCA2 genes are involved in some, but not all, forms of hereditary predisposition to breast cancer in the Turkish population.
Open Access
Germline mutations in the BRCA1 and BRCA2 genes in Turkish breast ovarian cancer patients
(John Wiley & Sons, Inc., 2003) Manguoglu, A. E.; Lüleci, G.; Özçelik, T.; Çolak, T.; Schayek, H.; Akaydin, M.; Friedman, E.
In this study we genotyped Turkish breast/ovarian cancer patients for BRCA1/BRCA2 mutations: protein truncation test (PTT) for exon 11 BRCA1 of and, multiplex PCR and denaturing gradient gel electrophoresis (DGGE) for BRCA2, complemented by DNA sequencing. In addition, a modified restriction assay was used for analysis of the predominant Jewish mutations: 185delAG, 5382InsC, Tyr978X (BRCA1) and 6174delT (BRCA2). Eighty three breast/ovarian cancer patients were screened: twenty three had a positive family history of breast/ovarian cancer, ten were males with breast cancer at any age, in eighteen the disease was diagnosed under 40 years of age, one patient had ovarian cancer in addition to breast cancer and one patient had ovarian cancer. All the rest (n=30) were considered sporadic breast cancer cases. Overall, 3 pathogenic mutations (3/53‐5.7%) were detected, all in high risk individuals (3/23–13%): a novel (2990insA) and a previously described mutation (R1203X) in BRCA1, and a novel mutation (9255delT) in BRCA2. In addition, three missense mutations [two novel (T42S, N2742S) and a previously published one (S384F)] and two neutral polymorphisms (P9P, P2532P) were detected in BRCA2. Notably none of the male breast cancer patients harbored any mutation, and none of the tested individuals carried any of the Jewish mutations. Our findings suggest that there are no predominant mutations within exon 11 of the BRCA1 and in BRCA2 gene in Turkish high risk families.
Open Access
HER2 and proliferation of wound-induced breast carcinoma
(The Lancet Publishing, 2003-11-01) Tez, M.; Göçmen, E.; Özçelik, T.
Open Access
Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1
(American Association for Cancer Research, 1999) Ricciardone, M. D.; Özçelik, T.; Cevher, B.; Özdaǧ, H.; Tuncer, M.; Gürgey, A.; Uzunalimoǧlu, O.; Çetinkaya, H.; Tanyeli, A.; Erken, E.; Öztürk, M.
Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer. The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown. We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1). DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T → Arg226Stop). Thus, a homozygous germ- line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1.
Open Access
Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer
(International Institute of Anticancer Research, 2004) Sevinç, A.; Yannoukakos, D.; Konstantopoulou, I.; Manguoglu, E.; Lüleci, G.; Çolak, T.; Akyerli, C.; Çolakoglu, G.; Tez, M.; Sayek, I.; Gerassimos, V.; Nasioulas, G.; Papadopoulou, E.; Florentin, L.; Kontogianni, E.; Bozkurt, B.; Kocabas, N. A.; Karakaya, A. E.; Yulug, I. G.; Özçelik, T.
Background: The RNASEL G1385A variant was recently found to be implicated in the development of prostate cancer. Considering the function of RNase L and the pleiotropic effects of mutations associated with cancer, we sought to investigate whether the RNASEL G1385A variant is a risk factor for breast cancer. Patients and Methods: A total of 453 breast cancer patients and 382 age- and sex-matched controls from Greece and Turkey were analyzed. Genotyping for the RNASEL G1385A variant was performed using an Amplification Refractory Mutation System (ARMS). Results: Statistical evaluation of the RNASEL G1385A genotype distribution among breast cancer patients and controls revealed no significant association between the presence of the risk genotype and the occurrence of breast cancer. Conclusion: Although an increasing number of studies report an association between the RNASEL G1385A variant and prostate cancer risk, this variant does not appear to be implicated in the development of breast cancer.
Open Access
MDM2 T309G polymorphism is associated with bladder cancer
(International Institute of Anticancer Research, 2006) Onat, O. E.; Tez, M.; Özçelik, T.; Törüner, G. A.
Recently, a functional T to G polymorphism at nucleotide 309 in the promoter region of the MDM2 gene (rs: 2279744, SNP 309) has been identified. This polymorphism has an impact on the expression of the MDM2 gene, which is a key negative regulator of the tumor suppressor molecule p53. The effect of T309G polymorphism of the MDM2 gene on bladder cancer susceptibility was investigated in a case-control study of 75 bladder cancer patients and 103 controls from Turkey. The G/G genotype exhibited an increased risk of 2.68 (95% CI, 1.34-5.40) for bladder cancer compared with the combination of low-risk genotypes T/T and T/G at this locus. These results show an association between MDM2 T309G polymorphism and bladder cancer in our study group. To the best of our knowledge, this is the first study reporting that MDM2 T309G polymorphism may be a potential genetic susceptibility factor for bladder cancer.
Open Access
Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences
(Wiley-Blackwell, 2017-09) Özçelik, T.
Open Access
Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder
(Cell Press, 2017) Patke, A.; Murphy, P. J.; Onat, O. E.; Krieger, A. C.; Özçelik, T.; Campbell, S. S.; Young, M. W.
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population. © 2017 Elsevier Inc.
Open Access
p53 codon 72 polymorphism in bladder cancer-No evidence of association with increased risk or invasiveness
(Springer, 2001) Törüner, G. A.; Uçar, A.; Tez, M.; Çetinkaya, M.; Özen, H.; Özçelik, T.
We studied the effect of the p53 gene Arg72Pro polymorphism on bladder cancer susceptibility in a case control study of 121 bladder cancer patients and 114 age-sex matched controls to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. Genomic DNA was obtained from venous blood samples for genotype determination by PCR and restriction digestion. The genotype frequencies in the patient group were Arg/Arg: 0.3553, Arg/Pro: 0.4711, Pro/Pro: 0.1736, and in the control group Arg/Arg: 0.3684, Arg/Pro: 0.4825, Pro/Pro: 0.1491. The distribution of genotypes between the two groups was not statistically different (χ2 = 0.260, df: 2, P = 0.878). The patient group was subdivided into two groups as superficial bladder cancer (n = 88) and invasive bladder cancer (n = 33), according to the presence of muscle invasion. The distribution of genotypes in the superficial group was Arg/Arg: 0.3409, Arg/Pro: 0.5114, Pro/Pro: 0.1477 and in the invasive group Arg/Arg: 0.3940, Arg/Pro: 0.3636, Pro/Pro: 0.2424. No association was observed with the invasiveness of the tumor (χ2 = 2.542, df: 2, P = 0.281). Stratification of the data by tobacco exposure did not result in a significant difference in genotype frequencies. These data do not support an association between the p53 Arg72Pro polymorphism and bladder cancer.