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Öğe A detailed in-silico analysis of potential gastric cancer molecular marker genes in the literature(Inderscience Enterprises Ltd, 2021) Aktas, Sedef Hande; Akin-Bali, Dilara Fatma; Yazici, OzanGenes found extremely important for the diagnosis and prognosis of Gastric Cancer (GC) in the literature between 2015 and 2020 were analysed in detail by in-silico methods. Thereby, broadly-based analysis of the genes was performed for future studies of GC. For this purpose, expression, pathological stage, Overall Survival (OS) and Disease Free Survival (DFS) plots were carried out with GEPIA web tool. PolyPhen-2 and SNAP tools were used to detect pathogenic impact of the mutations. As a result, COL10A1, SOX9, MTBP, CCL5, PSMB8 and PBK genes were found significant to distinguish individuals with GC from healthy individuals. PCDH9 and HGF genes were found significant for both OS and DFS. METTL3, COL10A1, USP3, CCL5, IMP3, CXCR6, PBK, HGF, MRC1, CD163, SSP1 genes were found correlated with the stage of GC. Effect of the mutations of PCDH9 and HGF genes, especially on the Kringle domain of HGF gene, were found pathogenic.Öğe A detailed understanding of the COL10A1 and SOX9 genes interaction based on potentially damaging mutations in gastric cancer using computational techniques(Taylor & Francis Inc, 2022) Aktas, Sedef Hande; Taskin-Tok, Tugba; Al-Khafaji, Khattab; Akin-Bali, Dilara FatmaGastric cancer (GC) has limited effective treatment options and is followed up with biomarkers that have insufficient sensitivity and specificity. Recent studies on Collagen Type X Alpha 1 Chain (COL10A1) show that the COL10A1 gene may be a diagnostic and/or prognostic biomarker for different cancer types. Moreover, its relationship with the Sex determining Region Y (SRY)-related HighMobility Group (HMG) box (SOX9) gene which is also a transcription factor, was discovered recently, and co-expression of these two genes are associated with the development of GC. However, to the best of our knowledge, there is no study in the literature on how potential damaging mutations in the SOX9 and COL10A1 genes can affect their interactions. The aim of this study is to investigate the interactions of wild-type and potentially damaging mutated structures of COL10A1 and SOX9 genes. Thus, outputs for drug development and therapeutic strategies for GC can be obtained. For this purpose, structure validation and energy minimization analyses as well as docking and binding affinity calculations were performed. As a result, it was found that all investigated mutations (P563S, I588L, T624A, H165R and N110T) increased the binding affinity between the COL10A1-SOX9 complex, especially the N110T and H165R mutants in SOX9. As a conclusion, the N110T and H165R mutants in SOX9 may contribute to tumor progression. Therefore, it is important to consider these mutations for future therapeutic strategies.Öğe Bioinformatic and computational analysis for predominant mutations of the Nrf2/Keap1 complex in pediatric leukemia(Taylor & Francis Inc, 2021) Akin-Bali, Dilara Fatma; Al-Khafaji, Khattab; Aktas, Sedef Hande; Taskin-Tok, TugbaThe levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor, which is the main regulator of antioxidant responses and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Our previous study has identified six novel changes in Nrf2/Keap1 pathway in pediatric ALL, which were described for the first time. These changes in the pathway are likely to alter the evolutionary process of amino acids and cause structural changes in the final products of genes. In this study, we aimed to compare the pathogenicity of eight determined mutations reported in our previous study by utilizing different programs with different algorithms and molecular dynamics simulation. Since it is too difficult to handle each existing mutation in a wet laboratory,in silicomethods may give suggestion to choose the important mutations for further analysis and to establish the appropriate patient population and conduct wet laboratory studies. For this purpose, four different algorithms were used to evaluate the effects of single amino acid mutation. In addition, root-mean-square deviation, root-mean-square fluctuation and free-energy landscape analyses were performed to observe stability, flexibility and energetically favorable conformations, respectively, for each amino acid mutation. As a result, our study emphasizes the importance of Keap1 mutations in pediatric ALL Nrf2/Keap1 pathway, a total of eight mutations, two of which were shown for the first time in our study. Especially the mutations in the Keap1 Broad-Complex, Tramtrack and Bric-a-brac domain are worthy of attention. Communicated by Ramaswamy H. Sarma.Öğe Bioinformatics analysis of GNAQ, GNA11, BAP1, SF3B1,SRSF2, EIF1AX, PLCB4, and CYSLTR2 genes and their role in the pathogenesis of Uveal Melanoma(Taylor & Francis Inc, 2021) Akin-Bali, Dilara FatmaUveal melanoma (UM) is the most common primary intraocular malignancy in adults, and its metastases are known to be fatal. It is critical to identify molecular markers to be used in potential prognostic evaluation for early diagnosis, treatment, and metastasis or to investigate all aspects of known genetic anomalies. Therefore, this study aimed to analyze the eight genes (GNAQ, GNA11, BAP1, SF3B1, SRSF2, EIF1AX, PLCB4, and CYSLTR2) that are associated with the most common genetic anomalies in UM from a molecular perspective. The genome sequences and expression profiles of 108 UM patients were obtained via bioinformatics tools that provide data from TCGA. The overall mutational load and the mutation patterns for eight genes, in particular, were thoroughly determined. Moreover, PolyPhen2 and SNAP(2) tools were used to estimate the oncogenic/pathogenic properties of identified mutations for UM. In addition to the mutation profile, the effects of the presence of a mutation on gene expression and survival were determined. Finally, STRING network analysis was performed to better understand the functional relationships of mutated proteins in cellular processes. There were 27 missense mutations, 16 frameshift mutations, six nonsense mutations, and three splice region mutations among the 52 mutations found in eight genes, and 26 of them had pathogenic properties. BAP1 m-RNA expression was significantly lower in tumors with the mutant genotype (p = .001). The impact of gene expression, which has poor prognostic importance, on survival is statistically significant for high-expressed BAP1 (p = .0015) and low-expressed CYSLTR2 (p = .0021). To assess the current state of this potentially devastating disease, a molecular perspective has been evaluated. Defining this molecular perspective can be useful in developing targeted drug therapies and personalized medicine.Öğe Comprehensive mutation analysis of the ras/raf/mek/erk pathway in paediatric leukaemia and significant inferences(Medcom Limited, 2021) Akin-Bali, Dilara Fatma; Aktas, Sedef Hande; Ozcan, Alper; Yilmaz, Ebru; Aydin, Firdevs; Gök, Veysel; Ünal, EkremObjectives: Leukaemia is the most common cancer among paediatric population accounting for about 30% of paediatric cancer. As it's known, germ line mutations increase the risk of development of haematopoietic malignancy in childhood and deregulation of the Rat Sarcoma Viral Proto-Oncogene/ Raf-1 Proto-Oncogene/Mitogen-Activated Protein Kinases/Extracellular Regulated Kinases (RAS/RAF/ MEK/ERK) pathway is often caused by somatic mutations in the genes coding proteins of KRAS, NRAS, FLT3, PTPN11 and BRAF. However, mutations in this pathway in paediatric Acute Lymphoblastic Leukaemia (ALL) have not been thoroughly investigated, yet. Methods: Specific exons of 7 significant genes which were frequently mutated in the RAS/RAF/MEK/ERK pathway were determined inclusively by DNA sequence analysis in 27 children with leukaemia. PolyPhen-2 and SNAP tools were used to verify and estimate the determined changes. Also, evolutionary conservation analysis was performed. Results: Seven changes out of 22 changes were identified for the first time in this study. ERK2 p.P319S (18.5%) mutation and KRAS splice site mutation (3.7%) were predicted to be pathogenic. ERK2 p.P319S mutations was found to be pathogenic and at the critical point on the aminoacid which is evalutionary conserved. Although the frequency of mutations in ERK2 is very low in cancers (0.88%), the frequency of ERK2 p.P319S missense change was detected in our study at a significant rate such as 18.5%. Conclusion: There is limited knowledge about ERK inhibitors in leukaemia. The low frequency of ERK gene compared to KRAS and NRAS genes does not make ERK mutations less important. Our findings indicate the importance of this pathway mutations in paediatric ALL and associated with high risk leukaemia group characteristics. Hence, it can be evaluated as a signalisation pathway to target pharmacologically. © 2021, Medcom Limited. All rights reserved.Öğe Evaluation of the role of Nrf2/Keap1 pathway-associated novel mutations and gene expression on antioxidant status in patients with deep vein thrombosis(Spandidos Publ Ltd, 2020) Akin-Bali, Dilara Fatma; Eroglu, Tamer; Ilk, Sedef; Egin, Yonca; Kankilic, TeomanDeep vein thrombosis (DVT) is a type of venous thromboembolism and a clinically complex vascular disease. Oxidative stress serves a key role in the pathogenesis of numerous cardiovascular diseases, particularly in endothelial dysfunction-associated syndromes. Nuclear factor erythroid-2-like 2(Nrf2) transcription factor is the primary regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). However, to the best of our knowledge, genetic abnormalites in the Nrf2/Keap1 pathway in DVT syndrome have not been thoroughly investigated. The aim of the present study was to investigate the association between the Nrf2/Keap1 pathway and antioxidant responses in DVT. Mutations and expression levels of genes involved in the Nrf2/Keap1 pathway were measured in 27 patients with DVT via DNA sequencing analysis and reverse transcription-quantitative PCR, respectively. The Polymorphism Phenotyping v2 program was used to identify the pathogenic mutations. Total antioxidant activity levels were determined by measuring the effect of serum samples from 27 patients with DVT on oxidation of the 2,2'-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid) system. A total of 23 mutations, including seven novel mutations, were detected in the Nrf2/Keap1 pathway in 24 (89%) of the 27 patients with DVT. Keap1 mRNA expression levels were significantly higher compared with Nrf2 expression levels in patients with DVT (P=0.02). Analysis of molecular characteristics and gene expression levels demonstrated that Nrf2/Keap1-associated mutations and total antioxidant levels can be used as precursor markers in the diagnosis of DVT.Öğe Genetic and epigenetic concept of SARS-CoV-2 targets in different renal cancer subtypes(Walter De Gruyter Gmbh, 2021) Akin-Bali, Dilara Fatma; Sagkan, Rahsan IlikciObjectives: Recent advances in defining the genetic landscape of has shown the host cell-SARS-CoV-2 interaction via ACE2 protein and the presence of at least three additional virus invasion genes including TMPRSS2, FURIN, CD147/BSG. In current study, we investigated the mutation and m-RNA expression patterns of target genes by evaluating the associations between genetic and epigenetic mechanisms in the target genes and susceptibility of SARS-CoV-2 infection of renal cancer subtypes. Methods: We investigated the mutation and m-RNA expression patterns of our target genes. The promoter methylation profiles of target genes were tested in the UALCAN database. Results: The total rate of carrying genetic anomaly in the target genes including was 1.6% and seven mutations, one of which had a pathogenic feature, were detected. The expression analysis results in renal cancer groups showed that while the KIRC and KIRP patients had a lower level of TMPRSS2 than the healthy control, their ACE2 level was high. KICH patients had a higher level of CD147/BSG expression than the healthy group. The promoter methylation levels of ACE2 in KIRC and KIRP were reduced. Conclusions: We concluded that renal cancer patients may be more sensitive to SARS-CoV-2 infection, which may worsen the prognosis.Öğe Genetic Profiling of Pediatric Patients with B-Cell Precursor Acute Lymphoblastic Leukemia(Georg Thieme Verlag Kg, 2023) Akin-Bali, Dilara Fatma; Erdogan, Beyza Doganay; Oner, Deniz Aslar; Mahmud, Akkan; Tasdelen, Serpil; Kurekci, Emin; Akar, NejatB-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous leukemia subgroup. It has multiple sub-types that are likely to be classified by prognostic factors. Following a systematic literature review, this study analyzed the genes correlated with BCP-ALL prognosis (IKZF1, PAX5, EBF1, CREBBP, CRLF2, JAK2, ERG, aCR4, ZAP70, VLA4, NF1, NR3C1, RB1, TSLP, ZNRF1, and FOXO3A), specifically their nucleotide variations and expression profiles in pediatric BCP-ALL samples. The study included 45 pediatric BCP-ALL patients with no cytogenetic anomaly and a control group of 10 children. The selected genes' hot-spot regions were sequenced using next-generation sequencing, while Polymorphism Phenotyping v2 and Supplemental Nutrition Assistance Program were used to identify pathogenic mutations. The expression analysis was performed using quantitative real-time polymerase chain reaction. The mutation analysis detected 328 variants (28 insertions, 47 indels, 74 nucleotide variants, 75 duplications, and 104 deletions). The most and least frequently mutated genes were IKZF1 and CREBBP, respectively. There were statistically significant differences between patients and controls for mutation distribution in eight genes (ERG, CRLF2, CREBBP, TSLP, JAK2, ZAP70, FOX03A, and NR3C1). The expression analysis revealed that JAK and ERG were significantly overexpressed in patients compared with controls (respectively, p = 0.004 and p =0.003). This study combined genes and pathways previously analyzed in pediatric BCP-ALL into one dataset for a comprehensive analysis from the same samples to unravel candidate prognostic biomarkers. Novel mutations were identified in all of the studied genes.Öğe Genetic Variations in Nrf2-Keap1 Complex: A Step towards Understanding Cancer Resistance in Blind Mole Rats Cytotypes(Pleiades Publishing Inc, 2019) Akin-Bali, Dilara Fatma; Kankilic, TeomanThe Nrf2-Keap1 regulation system plays a crucial role in cytoprotection against electrophilic/oxidative stress. Previous studies have identified missense mutations in Nrf2/Keap1 complex which abolish its activity. The amino acid corresponding to codon 212 in Keapl's IVR domain is conserved as tyrosine (Y) among different mammalian species whereas only Nannospalax and two other species carry a cysteine (C) residue at this position. These species include Sperm whale and European hedgehog that live in hypoxic environment. In this study, we examined genetic variations in Nrf2-Keap1 complex, which was reported to be important in cancer pathogenesis in previous studies, in cancer resistant blind mole rat species with varying chromosome numbers (2n: 46-60) that we collected from different regions in Turkey. This study was the first to provide information on genetic variants in Nrf2/Keap1 complex of blind mole rats living in Turkey.Öğe Identification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia(Taylor & Francis Inc, 2020) Akin-Bali, Dilara Fatma; Aktas, Sedef Hande; Unal, Mehmet Altay; Kankilic, TeomanAcute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells, characterized by a wide range of biological and clinical heterogeneity. Oxidative stress is a common problem observed in carcinogenesis and it is involved in developing treatment resistance. Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor is the main regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Recently, many studies have shown that most of the genes in the Nrf2/Keap1/nuclear factor kappa-B (NF-kappa B)/phosphotyrosine-independent ligand for the Lck SH2 domain Of 62 KDa (p62) pathway show abnormally high mutational variations in cancer. However, variations in the Nrf2/Keap1/NF-kappa B1/p62 pathway in pediatric ALL have not been thoroughly investigated, yet. Thirty children, who were diagnosed with pediatirc ALL were included in the study. The Nrf2/Keap1/NF-kappa B1/p62 pathway variants were analyzed by DNA sequencing analysis. The PolyPhen-2 program was used for identifying pathogenic mutations. Our study examined the molecular dynamics (MD) perspectives of the effect of A159T and E121K mutations on protein stability for the first time in the literature by using the GROMACS45 software package utilizing the OPSLAA force field. Of the detected 17 nucleotide changes, 6 were novel. The study predicted the potential pathological effect of two mutations p. A159T and p.E121K in the Keap1 gene. The MD perspectives revealed that the E121K mutant's observed structural behavior accounted for the key role of His-129 and E121K, where E121K exhibited much higher drift compared to His-129. For a future perspective, it would be meaningful to study the protein-small molecule interactions of the Keap1 protein to elaborate on the drug effects in patients carrying these mutations.Öğe Structural variations and expression profiles of the SARS-CoV-2 host invasion genes in lung cancer(Wiley, 2020) Ilikci Sagkan, Rahsan; Akin-Bali, Dilara FatmaRecent days have seen growing evidence of cancer's susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of the effect of genomic differences on the virus' entrance genes in lung cancer. Genetic confirmation of the hypotheses regarding gene expression and mutation pattern of target genes, including angiotensin-converting enzyme-2 (ACE2), transmembrane serine protease 2 (TMPRSS2), basigin (CD147/BSG) and paired basic amino acid cleaving enzyme (FURIN/PCSK3), as well as correlation analysis, was done in relation to lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) using in silico analysis. Not only were gene expression and mutation patterns detected, but also there were correlation and survival analysis between ACE2 and other target genes expression levels. The total genetic anomaly carrying rate of target genes, including ACE2, TMPRSS2, CD147/BSG, and FURIN/PCSK3, was determined as 8.1% and 21 mutations were detected, with 7 of these mutations having pathogenic features. p.H34N on the RBD binding residues for SARS-CoV-2 was determined in our LUAD patient group. According to gene expression analysis results, though the TMPRSS2 level was statistically significantly decreased in the LUSC patient group compared to healthy control, the ACE2 level was determined to be high in LUAD and LUSC groups. There were no meaningful differences in the expression of CD147 and FURIN genes. The challenge for today is building the assessment of genomic susceptibility to COVID-19 in lung cancer, requiring detailed experimental laboratory studies, in addition to in silico analyses, as a way of assessing the mechanism of novel virus invasion that can be used in the development of effective SARS-CoV-2 therapy.
