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      Shelterin complex gene: Prognosis and therapeutic vulnerability in cancer

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          Abstract

          Telomere encompasses a (TTAGGG)n tandem repeats, and its dysfunction has emerged as the epicenter of driving carcinogenesis by promoting genetic instability. Indeed, they play an essential role in stabilizing chromosomes and therefore protecting them from end-to-end fusion and DNA degradation. Telomere length homeostasis is regulated by several key players including shelterin complex genes, telomerase, and various other regulators. Targeting these regulatory players can be a good approach to combat cancer as telomere length is increasingly correlated with cancer initiation and progression. In this review, we have aimed to describe the telomere length regulator's role in prognostic significance and important drug targets in breast cancer. Moreover, we also assessed alteration in telomeric function by various telomere length regulators and compares this to the regulatory mechanisms that can be associated with clinical biomarkers in cancer. Using publicly available software we summarized mutational and CpG island prediction analysis of the TERT gene breast cancer patient database. Studies have reported that the TERT gene has prognostic significance in breast cancer progression however mechanistic approaches are not defined yet. Interestingly, we reported using the UCSC Xena web-based tool, we confirmed a positive correlation of shelterin complex genes TERF1 and TERF2 in recurrent free survival, indicating the critical role of these genes in breast cancer prognosis. Moreover, the epigenetic landscape of DNA damage repair genes in different breast cancer subtypes also being analyzed using the UCSC Xena database. Together, these datasets provide a comprehensive resource for shelterin complex gene profiles and define epigenetic landscapes of DNA damage repair genes which reveals the key role of shelterin complex genes in breast cancer with the potential to identify novel and actionable targets for treatment.

          Highlights

          • Assessed alteration in telomeric function by various telomere length regulators and compares its involvement in regulatory mechanisms that can be associated with clinical biomarkers in cancer.

          • Prognostic value of each Shelterin complex genes were determined in breast cancer using the Kaplan–Meier plotter database.

          • Summarizes telomere length regulators role in prognostic significance and important drug targets.

          • Identified positive correlation of TERF1 and TERF2 in recurrent free survival, indicating the critical role of these genes in breast cancer prognosis.

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          Most cited references127

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

            The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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              The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

              The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. © 2012 AACR.
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                Author and article information

                Contributors
                Journal
                Biochem Biophys Rep
                Biochem Biophys Rep
                Biochemistry and Biophysics Reports
                Elsevier
                2405-5808
                02 February 2021
                July 2021
                02 February 2021
                : 26
                : 100937
                Affiliations
                [a ]Department of Biosciences, Manipal University Jaipur, Rajasthan, India
                [b ]Department of Physiology, Government Medical College, Kannauj, Uttar Pradesh, India
                [c ]Department of Neurology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
                Author notes
                []Corresponding author . Cancer Research Lab, Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Near JVK Toll Plaza, Jaipur-Ajmer Expressway, Jaipur-303007, Rajasthan, India., rajeev.mishra@ 123456jaipur.manipal.edu rajeev.cres@ 123456gmail.com
                Article
                S2405-5808(21)00031-5 100937
                10.1016/j.bbrep.2021.100937
                7859307
                33553693
                6cdf9e4a-64f8-4685-bd8e-8cbf5e87d033
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 3 September 2020
                : 8 January 2021
                : 25 January 2021
                Categories
                Review Article

                telomere,dna damage,htert,shelterin complex
                telomere, dna damage, htert, shelterin complex

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