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      Telomere Maintenance Mechanisms in Cancer

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          Abstract

          Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter ( TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

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          Most cited references384

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          (2017)
          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            Telomeres and human disease: ageing, cancer and beyond.

            Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
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              Alternative lengthening of telomeres: models, mechanisms and implications.

              Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10-15% of cancers - including some with particularly poor outcome - it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                03 May 2018
                May 2018
                : 9
                : 5
                : 241
                Affiliations
                [1 ]Cancer Signaling and Metabolism Group, Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135 Porto, Portugal; tgaspar@ 123456ipatimup.pt (T.B.G.); asa@ 123456ipatimup.pt (A.S.); jmlopes@ 123456ipatimup.pt (J.M.L.); ssimoes@ 123456ipatimup.pt (M.S.-S.); jvinagre@ 123456ipatimup.pt (J.V.)
                [2 ]Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal
                [3 ]Medical Faculty of University of Porto (FMUP), 4200-139 Porto, Portugal
                [4 ]Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313 Porto, Portugal
                [5 ]Department of Pathology and Oncology, Centro Hospitalar São João, 4200-139 Porto, Portugal
                Author notes
                [* ]Correspondence: psoares@ 123456ipatimup.pt ; Tel.: +351-225570700
                [†]

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0002-7757-7401
                https://orcid.org/0000-0001-8597-3474
                https://orcid.org/0000-0003-1613-1235
                https://orcid.org/0000-0001-9607-6998
                https://orcid.org/0000-0002-0871-1427
                Article
                genes-09-00241
                10.3390/genes9050241
                5977181
                29751586
                dbf61514-b9b5-49dd-9da2-59aae674c025
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 March 2018
                : 23 April 2018
                Categories
                Review

                cancer,telomere,telomerase,promoter,tert,terc,alternative lengthening of telomeres (alt),telomere maintenance mechanism (tmm),non-defined telomere maintenance mechanism (ndtmm)

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