Person: ARĞA, KAZIM YALÇIN
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ARĞA
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KAZIM YALÇIN
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Publication Metadata only Toward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing(2023-09-01) ERDOĞAN, ONUR; ERZİK, CAN; ARĞA, KAZIM YALÇIN; BAYRAKLI, FATİH; ERDOĞAN O., Özkaya Ş. Ç., ERZİK C., Bilguvar K., ARGA K. Y., BAYRAKLI F.Precision/personalized medicine in oncology has two key pillars: molecular profiling of the tumors and personalized reporting of the results in ways that are clinically contextualized and triangulated. Moreover, neurosurgery as a field stands to benefit from precision/personalized medicine and new tools for reporting of the molecular findings. In this context, glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Precision/personalized medicine has emerged as a promising approach for personalized therapy in GBM. In this study, we performed whole exome sequencing of tumor tissue samples from six newly diagnosed GBM patients and matched nontumor control samples. We report here the genetic alterations identified in the tumors, including single nucleotide variations, insertions or deletions (indels), and copy number variations, and attendant mutational signatures. Additionally, using a personalized cancer genome-reporting tool, we linked genomic information to potential therapeutic targets and treatment options for each patient. Our findings revealed heterogeneity in genetic alterations and identified targetable pathways, such as the PI3K/AKT/mTOR pathway. This study demonstrates the prospects of precision/personalized medicine in GBM specifically, and neurosurgical oncology more generally, including the potential for genomic profiling coupled with personalized cancer genome reporting. Further research and larger studies are warranted to validate these findings and advance the treatment options and outcomes for patients with GBM.Publication Open Access Editorial: Omics integration and network medicine to decipher human complex diseases(2023-01-01) ARĞA, KAZIM YALÇIN; Zanfardino M., Babbi G., ARĞA K. Y., Pane K.Publication Metadata only The versatility of plectin in cancer: A pan-cancer analysis on potential diagnostic and prognostic impacts of plectin isoforms(2023-06-01) ARĞA, KAZIM YALÇIN; Gundesli H., Kori M., ARGA K. Y.Plectin, encoded by PLEC, is a cytoskeletal and scaffold protein with a number of unique isoforms that act on various cellular functions such as cell adhesion, signal transduction, cancer cell invasion, and migration. While plectin has been shown to display high expression and mislocalization in tumor cells, our knowledge of the biological significance of plectin and its isoforms in tumorigenesis remain limited. In this study, we first performed pathway enrichment analysis to identify cancer hallmark proteins associated with plectin. Then, a pan-cancer analysis was performed using RNA-seq data collected from the Cancer Genome Atlas (TCGA) to detect the mRNA expression levels of PLEC and its transcript isoforms, and the prognostic as well as diagnostic significance of the transcript isoforms was evaluated considering cancer stages. We show here that several tissue specific PLEC isoforms are dysregulated in different cancer types and stages but not the expression of PLEC. Among them, PLEC 1d and PLEC 1f are potential biomarker candidates and call for further translational and personalized medicine research. This study makes a contribution as a stride to unravel the molecular mechanisms underpinning plectin isoforms in cancer development and progression by revealing the potent plectin isoforms in different stages of cancer as potential early cancer detection biomarkers. Importantly, uncovering how plectin isoforms guide malignancy and particular cancer types by comprehensive functional studies might open new avenues toward novel cancer therapeutics.Publication Metadata only Past, present, and future of therapies for pituitary neuroendocrine tumors: need for omics and drug repositioning guidance(2022-03-01) ERDOĞAN, ONUR; ARĞA, KAZIM YALÇIN; BOZKURT, SÜHEYLA; BAYRAKLI, FATİH; YILMAZ, BETÜL; TURANLI, BESTE; Aydin B., Yildirim E., ERDOĞAN O., ARĞA K. Y., Yilmaz B., BOZKURT S., BAYRAKLI F., TURANLI B.Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs\" treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.Publication Metadata only Systems Biomarkers, Artificial Intelligence, and One Health Vision Can Help Fight Antimicrobial Resistance(2023-02-01) KULA, CEYDA; ARĞA, KAZIM YALÇIN; KULA C., ARĞA K. Y.Publication Metadata only Acute myeloid leukemia: New multiomics molecular signatures and implications for systems medicine diagnostics and therapeutics innovation(2022-07-01) ARĞA, KAZIM YALÇIN; TURANLI, BESTE; YILMAZ, BETÜL; Kelesoglu N., Kori M., TURANLI B., ARĞA K. Y., Yilmaz B., Duru O. A.Acute myeloid leukemia (AML) is a common, complex, and multifactorial malignancy of the hematopoietic system. AML diagnosis and treatment outcomes display marked heterogeneity and patient-to-patient variations. To date, AML-related biomarker discovery research has employed single omics inquiries. Multiomics analyses that reconcile and integrate the data streams from multiple levels of the cellular hierarchy, from genes to proteins to metabolites, offer much promise for innovation in AML diagnostics and therapeutics. We report, in this study, a systems medicine and multiomics approach to integrate the AML transcriptome data and reporter biomolecules at the RNA, protein, and metabolite levels using genome-scale biological networks. We utilized two independent transcriptome datasets (GSE5122, GSE8970) in the Gene Expression Omnibus database. We identified new multiomics molecular signatures of relevance to AML: miRNAs (e.g., mir-484 and miR-519d-3p), receptors (ACVR1 and PTPRG), transcription factors (PRDM14 and GATA3), and metabolites (in particular, amino acid derivatives). The differential expression profiles of all reporter biomolecules were crossvalidated in independent RNA-Seq and miRNA-Seq datasets. Notably, we found that PTPRG holds important prognostication potential as evaluated by Kaplan-Meier survival analyses. The multiomics relationships unraveled in this analysis point toward the genomic pathogenesis of AML. These multiomics molecular leads warrant further research and development as potential diagnostic and therapeutic targets.Publication Metadata only Precision diagnosis of maturity-onset diabetes of the young with next-generation sequencing: Findings from the MODY-IST study in adult patients(2022-04-01) ARĞA, KAZIM YALÇIN; Aydogan H. Y., Gul N., Demirci D. K., Mutlu U., Gulfidan G., ARĞA K. Y., ÖZDER A., ÇAMLI A. A., Tutuncu Y., Ozturk O., et al.Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as \"deleterious\" as well as those predicted as \"benign.\" Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.Publication Metadata only Driving precision oncology to clinical practice: The road ahead from biomarker validation to clinical decision systems(2022-06-01) ARĞA, KAZIM YALÇIN; YILMAZ, BETÜL; Yilmaz B., ARĞA K. Y.Publication Metadata only A differential transcriptional regulome approach to unpack cancer biology: insights on renal cell carcinoma subtypes(2023-01-01) ARĞA, KAZIM YALÇIN; Caliskan A., ARGA K. Y.Cancer research calls for new approaches that account for the regulatory complexities of biology. We present, in this study, the differential transcriptional regulome (DIFFREG) approach for the identification and prioritization of key transcriptional regulators and apply it to the case of renal cell carcinoma (RCC) biology. Of note, RCC has a poor prognosis and the biomarker and drug discovery studies to date have tended to focus on gene expression independent from mutations and/or post-translational modifications. DIFFREG focuses on the differential regulation between transcription factors (TFs) and their target genes rather than differential gene expression and integrates transcriptome profiling with the human transcriptional regulatory network to analyze differential gene regulation between healthy and RCC cases. In this study, RNA-seq tissue samples (n = 1020) from the Cancer Genome Atlas (TCGA), including healthy and tumor subjects, were integrated with a comprehensive human TF-gene interactome dataset (1122603 interactions between 1289 TFs and 25177 genes). Comparative analysis of DIFFREG profiles, consisting of perturbed TF-gene interactions, from three common subtypes (clear cell RCC, papillary RCC and chromophobe RCC) revealed subtype-specific alterations, supporting the hypothesis that these signatures in the transcriptional regulome profiles may be considered potential biomarkers that may play an important role in elucidating the molecular mechanisms of RCC development and translating knowledge about the genetic basis of RCC into the clinic. In addition, these indicators may help oncologists make the best decisions for diagnosis and prognosis management.Publication Metadata only A Transcriptomic and reverse-engineering strategy reveals molecular signatures of arachidonic acid metabolism in 12 cancers(2023-02-01) ARĞA, KAZIM YALÇIN; KUBAT ÖKTEM E., Aydin B., Gulfidan G., ARĞA K. Y.Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2 alpha, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.