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Item IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation(NATURE PUBLISHING GROUP, 2016-01-01) Oktay, Yavuz; Ulgen, Ege; Can, Ozge; Akyerli, Cemaliye B.; Yuksel, Sirin; Erdemgil, Yigit; Durasi, I. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Sevin; Ozpinar, Aysel; Huse, Jason T.; Sav, M. Aydin; Flanagan, Adrienne; Gunel, Murat; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayThe single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52Item PTPRD is Homozygously Deleted and Epigenetically Downregulated in Human Hepatocellular Carcinomas(MARY ANN LIEBERT, INC, 2015-01-01) Acun, Tolga; Demir, Kubilay; Oztas, Emin; Arango, Diego; Yakicier, M. CengizPTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5 ` UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5\% of cell lines and 82.6\% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2\% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology.Item Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms(MDPI, 2020-01-01) Ulgen, Ege; Karacan, Sila; Gerlevik, Umut; Can, Ozge; Bilguvar, Kaya; Oktay, Yavuz; B. Akyerli, Cemaliye; K. Yuksel, Sirin; E. Danyeli, Ayca; Tihan, Tarik; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayLittle is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and ``Others{''} differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.Item Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma(BMC, 2021-01-01) Ulgen, Ege; Can, Ozge; Bilguvar, Kaya; Boylu, Cemaliye Akyerli; Yuksel, Sirin Kilicturgay; Danyeli, Ayca Ersen; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, KorayBackground In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. Methods The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. Results The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14-33) variants per patient was reported. There was a median of 6 (0-590) reported somatic short variants per tumor. A median of 19 (0-94) broad SCNAs and a median of 6 (0-12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38\%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9\%). Conclusions We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.Item Dealing with the gray zones in the management of gastric cancer: The consensus statement of the Istanbul Group(AVES, 2019-01-01) Aytac, Erman; Aslan, Fatih; Cicek, Bahattin; Erdamar, Sibel; Gurses, Bengi; Guven, Koray; Falay, Okan; Karahasanoglu, Tayfun; Selcukbiricik, Fatih; Selek, Ugur; Atalar, Banu; Balik, Emre; Tozun, Nurdan; Rozanes, Izzet; Arican, Ali; Hamzaoglu, Ismail; Baca, Bilgi; Mandell, Nil Molinas; Saruc, Murat; Goksel, Suha; Demir, Gokhan; Agaoglu, Fulya; Yakicier, Cengiz; Ozbek, Ugur; Ozben, Volkan; Ozyar, Enis; Guner, Ahmet Levent; Er, Ozlem; Kaban, Kerim; Bolukbasi, Yasemin; Bugra, Dursun; Ahishali, Emel; Asian, Fatih; Boz-bas, Aysun; Hamzaoglu, Hulya; Karaman, Ahmet; Kucukmetin, Nurten Turkel; Vardareli, Eser Kutsal; Onder, Fatih Oguz; Sisman, Gurhan; Tiftikci, Arzu; Unal, Hakan Umit; Yapali, Suna; Acar, Sami; Agcaoglu, Orhan; Aghayeva, Afag; Akyuz, Ali; Atasoy, Deniz; Batik, Emre; Bayraktar, Ilknur Erenler; Bayram, Onur; Bilgic, Cagri; Bilgin, Ismail Ahmet; Can, Ugur; Dulgeroglu, Onur; Durukan, Ugur; Gencosmanoglu, Rasim; Gonenc, Murat; Gurbuz, Bulent; Kaya, Mesut; Omarov, Nail; Ozben, Volkan; Ozgur, Ilker; Ozoran, Emre; Sobutay, Erman; Uras, Cihan; Uymaz, Derya; Zenger, Serkan; Ozbek, Ugur; Yakicier, M. Cengiz; Afsar, Cigdem Usul; Bozkurt, Mustafa; Demir, Atakan; Er, Ozlem; Kanitez, Metin; Korkmaz, Taner; Mandel, Nil Molina; Mert, Askhan Guven; Ozer, Leyla; Sonmez, Ozlem; Tunali, Didem; Uluc, Basak Oyan; Yazar, Aziz; Yildiz, Ibrahim; Demirkurek, Cengiz; Guner, Ahmet Levent; Vardareli, Erkan; Armutlu, Aye; Baba, Fisun; Ersozlu, Ilker; Kapran, Yersu; Sahin, Davut; Abacioglu, Mehmet Ufuk; Bese, Nuran; Durankus, Nilufer Kilic; Gural, Zeynep; Ozyar, Enis; Sengoz, Meric; Sezen, Duygu; Caliskan, Can; Guven, Koray; Karaaslan, Ercan; Kizilkaya, Esref; Suleyman, Erdogan; Grp, IstanbulThe geographical location and differences in tumor biology significantly change the management of gastric cancer. The prevalence of gastric cancer ranks fifth and sixth among men and women, respectively, in Turkey. The international guidelines from the Eastern and Western countries fail to manage a considerable amount of inconclusive issues in the management of gastric cancer. The uncertainties lead to significant heterogeneities in clinical practice, lack of homogeneous data collection, and subsequently, diverse outcomes. The physicians who are professionally involved in the management of gastric cancer at two institutions in Istanbul, Turkey, organized a consensus meeting to address current problems and plan feasible, logical, measurable, and collective solutions in their clinical practice for this challenging disease. The evidence-based data and current guidelines were reviewed. The gray zones in the management of gastric cancer were determined in the first session of this consensus meeting. The second session was constructed to discuss, vote, and ratify the ultimate decisions. The identification of the T stage, the esophagogastric area, imaging algorithm for proper staging and follow-up, timing and patient selection for neoadjuvant treatment, and management of advanced and metastatic disease have been accepted as the major issues in the management of gastric cancer. The recommendations are presented with the percentage of supporting votes in the results section with related data.Item Serum Bone Markers Levels and Bone Mineral Density in Familial Mediterranean Fever(SOC PHYSICAL THERAPY SCIENCE, 2014-01-01) Aydin, Teoman; Taspinar, Ozgur; Akbal, Yildiz; Peru, Celaleddin; Guler, Mustafa; Uysal, Omer; Yakicier, M. Cengiz{[}Purpose] The aim of this study was to measure bone mineral density, serum and urinary bone turnover parameters, and to evaluate the influence of demographic and genetic factors on these parameters in FMF patients. {[}Subjects and Methods] Twenty-seven attack-free patients who were diagnosed with FMF (in accordance with Tel Hashomer criteria) were recruited at outpatient rheumatology clinics. We investigated whether there were any differences between the FMF patients and a control group in terms of lumbar and femur bone mineral density (BMD), standard deviation scores (Z scores and T scores) and bone markers. {[}Results] In terms of the median values of lumbar BMD (p = 0.21), lumbar T (p = 0.098) and Z (p = 0.109) scores, femoral neck BMD, femoral T and Z scores and total femur BMD, T (p = 0.788) and Z scores, there were no significant differences. {[}Conclusion] In our study, no statistically significant differences were found between FMF patients and a control group in terms of osteoporosis. The 25-OH vitamin D was found to be significantly lower in FMF patients than in the control group.Item Lack of hotspot mutations other than TP53 R249S in aflatoxin B1 associated hepatocellular carcinoma(WALTER DE GRUYTER GMBH, 2020-01-01) Akyerli, Cemaliye B.; Yuksel, Sirin K.; Yakicier, M. CengizObjective: Despite the recent advances in diagnosis and treatment of hepatocellular carcinoma (HCC), it is still a major health problem. Therefore, understanding the molecular mechanism is very important. Our aim is to investigate the molecular basis of aflatoxin B1 (AFB1) induced HCC other than the hotspot TP53 p.Arg249Ser (c.747G>T) (R249S) mutation. Methods: 525 genes previously reported to be involved in carcinogenesis with mutations in different cancer types were analyzed by next generation sequencing for 525 cancer-gene panel (Roche/NimbleGen) in one tumor sample (T29) and one cell line (MAHLAVU) carrying TP53 R249S mutation. Additionally, ARID2 and BCORL1 genes were analyzed by Sanger sequencing for MAHLAVU and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5 (PLC/PRF/5) cell lines. Results: No other common gene mutations were found in the analyzed T29 and MAHLAVU samples and also no genetic variation possibly associated with AFB1 was detected in PLC/PRF/5 cell line and 68 COSMIC HCC samples. Likewise, no pathogenic mutation was detected in ARID2 and BCORL1 genes of MAHLAVU and PLC/PRF/5 cell lines. Conclusion: No fingerprint mutations were detected in the analyzed genes. To the best of our knowledge, other hotspot mutations appear to be absent if not at a very low frequency in HCC carrying TP53 R249S mutation.