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Tsatsakis A, Oikonomopoulou T, Nikolouzakis TK, Vakonaki E, Tzatzarakis M, Flamourakis M, Renieri E, Fragkiadaki P, Iliaki E, Bachlitzanaki M, Karzi V, Katsikantami I, Kakridonis F, Hatzidaki E, Tolia M, Svistunov AA, Spandidos DA, Nikitovic D, Tsiaoussis J, Berdiaki A. Role of telomere length in human carcinogenesis (Review). Int J Oncol 2023; 63:78. [PMID: 37232367 PMCID: PMC10552730 DOI: 10.3892/ijo.2023.5526] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
Cancer is considered the most important clinical, social and economic issue regarding cause‑specific disability‑adjusted life years among all human pathologies. Exogenous, endogenous and individual factors, including genetic predisposition, participate in cancer triggering. Telomeres are specific DNA structures positioned at the end of chromosomes and consist of repetitive nucleotide sequences, which, together with shelterin proteins, facilitate the maintenance of chromosome stability, while protecting them from genomic erosion. Even though the connection between telomere status and carcinogenesis has been identified, the absence of a universal or even a cancer‑specific trend renders consent even more complex. It is indicative that both short and long telomere lengths have been associated with a high risk of cancer incidence. When evaluating risk associations between cancer and telomere length, a disparity appears to emerge. Even though shorter telomeres have been adopted as a marker of poorer health status and an older biological age, longer telomeres due to increased cell growth potential are associated with the acquirement of cancer‑initiating somatic mutations. Therefore, the present review aimed to comprehensively present the multifaceted pattern of telomere length and cancer incidence association.
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Affiliation(s)
- Aristidis Tsatsakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | - Tatiana Oikonomopoulou
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion
| | - Taxiarchis Konstantinos Nikolouzakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion
| | - Elena Vakonaki
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | - Manolis Tzatzarakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | | | - Elisavet Renieri
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | | | - Evaggelia Iliaki
- Laboratory of Microbiology, University Hospital of Heraklion, 71500 Heraklion
| | - Maria Bachlitzanaki
- Department of Medical Oncology, Venizeleion General Hospital of Heraklion, 71409 Heraklion
| | - Vasiliki Karzi
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | - Ioanna Katsikantami
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion
| | - Fotios Kakridonis
- Department of Spine Surgery and Scoliosis, KAT General Hospital, 14561 Athens
| | - Eleftheria Hatzidaki
- Department of Neonatology and Neonatal Intensive Care Unit (NICU), University Hospital of Heraklion, 71500 Heraklion
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, 71110 Heraklion, Greece
| | - Andrey A. Svistunov
- Department of Pharmacology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dragana Nikitovic
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - John Tsiaoussis
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion
| | - Aikaterini Berdiaki
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
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Myung JK, Kwak BK, Lim JA, Lee MC, Kim MJ. TERT Promoter Mutations and Tumor Persistence/Recurrence in Papillary Thyroid Cancer. Cancer Res Treat 2015; 48:942-7. [PMID: 26727717 PMCID: PMC4946362 DOI: 10.4143/crt.2015.362] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/17/2015] [Indexed: 01/20/2023] Open
Abstract
PURPOSE A telomerase reverse transcriptase (TERT) promoter mutation was identified in thyroid cancer. This TERT promoter mutation is thought to be a prognostic molecular marker, because its association with tumor aggressiveness, persistence/recurrence, and disease-specific mortality in papillary thyroid carcinoma (PTC) has been reported. In this study, we attempted to determine whether the impact of the TERT promoter mutation on PTC persistence/recurrence is independent of clinicopathological parameters. MATERIALS AND METHODS Using propensity score matching, 39 patients with PTC persistence or recurrence were matched with 35 patients without persistence or recurrence, with a similar age, sex, tumor size, multifocality, bilaterality, extrathyroidal extension, and lymph node metastasis. The TERT promoter and the BRAF V600E mutations were identified from PTC samples. RESULTS The TERT promoter mutation was detected in 18% of PTC patients (13/74). No significant difference in the frequency of the TERT promoter mutation was observed between the persistence/recurrence group and the non-recurrence group. CONCLUSION These results suggest that the prognostic implications of the TERT promoter mutation are dependent on clinicopathological parameters.
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Affiliation(s)
- Jae Kyung Myung
- Department of Pathology, Korea Cancer Center Hospital, Seoul, Korea
| | - Byung Kuk Kwak
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| | - Jung Ah Lim
- Department of Internal Medicine, National Medical Center, Seoul, Korea
| | - Myung-Chul Lee
- Department of Otorhinolaryngology, Korea Cancer Center Hospital, Seoul, Korea
| | - Min Joo Kim
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
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Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, Castro P, Prazeres H, Lima J, Amaro T, Lobo C, Martins MJ, Moura M, Cavaco B, Leite V, Cameselle-Teijeiro JM, Carrilho F, Carvalheiro M, Máximo V, Sobrinho-Simões M, Soares P. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014; 99:E754-65. [PMID: 24476079 PMCID: PMC4191548 DOI: 10.1210/jc.2013-3734] [Citation(s) in RCA: 399] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. OBJECTIVES We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). DESIGN This was a retrospective observational study. SETTING AND PATIENTS We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. MAIN OUTCOME MEASURES Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. RESULTS TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01-53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36-415.76; P = .03) in PTCs. CONCLUSIONS TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.
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Affiliation(s)
- Miguel Melo
- Institute of Molecular Pathology and Immunology of the University of Porto (M.Me., A.G.d.R., J.V., R.B., J.P., C.T., R.C., A.A., C.S., C.E., P.C., H.P., J.L., V.M., M.S.-S., P.S.), 4200-465 Porto, Portugal; Medical Faculty, University of Porto (A.G.d.R., C.T.), 4200-139 Porto, Portugal; Institute of Biomedical Sciences of Abel Salazar, University of Porto (J.V., A.A.), 4050-313 Porto, Portugal; Department of Pathology and Oncology, Medical Faculty, University of Porto (J.L., V.M., M.S.-S., P.S.), 4200-139 Porto, Portugal; Departments of Endocrinology, Diabetes, and Metabolism (M.Me., F.C., M.C.) and Pathology (M.J.M.), University and Hospital Center of Coimbra, 3000-075 Coimbra, Portugal; Unit of Endocrinology (M.Me., M.C.), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; School of Allied Health Sciences, ESTSP - Escola Superior de Tecnologia da Saúde do Porto (R.C.), Polytechnic of Porto, 4400-330 Vila Nova de Gaia, Portugal; Portuguese Institute of Oncology (H.P.), Coimbra Center, 3000-075 Coimbra, Portugal; Department of Pathology (T.A.), Hospital Pedro Hispano, 4464-513 Matosinhos, Portugal; Department of Pathology (C.L.), Portuguese Institute of Oncology, Porto Center, 4200-072 Porto, Portugal; Center for Investigation of Molecular Pathobiology (M.Mo., B.C., V.L.) and Department of Endocrinology (V.L.), Portuguese Institute of Oncology, Lisbon Center, 1099-023 Lisbon, Portugal; Center for the Study of Chronic Diseases (M.Mo., B.C., V.L.), Faculty of Medical Sciences, University of Lisbon, 1099-085 Lisbon, Portugal; Department of Pathology (J.M.C.-T.), Clinical University Hospital, Servicio Gallego de Salud - SERGAS, Medical Faculty, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; and Department of Pathology (M.S.-S.), Hospital S. João, 4200-319 Porto, Portugal
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Soares P, Lima J, Preto A, Castro P, Vinagre J, Celestino R, Couto JP, Prazeres H, Eloy C, Máximo V, Sobrinho-Simões M. Genetic alterations in poorly differentiated and undifferentiated thyroid carcinomas. Curr Genomics 2012; 12:609-17. [PMID: 22654560 PMCID: PMC3271313 DOI: 10.2174/138920211798120853] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 08/29/2011] [Accepted: 08/30/2011] [Indexed: 12/20/2022] Open
Abstract
Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC).It is usually accepted that PDTC and UTC occur either de novo or progress from a pre-existing well differentiated carcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplastic development. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming that PDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC and UTC would harbour genetic alterations that are typical of PTC and FTC. This is the case for some molecular markers (BRAF and NRAS) that are present in WDTC, PDTC and UTC. Other genes, namely P53, are almost exclusively detected in less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC. Thyroid-specific rearrangements RET/PTC and PAX8/PPARγ, on the other hand, are rarely found in PDTC and UTC, suggesting that these genetic alterations do not predispose cells to dedifferentiation. In the present review we have summarized the molecular changes associated with the two most aggressive types of thyroid cancer.
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Affiliation(s)
- Paula Soares
- Institute of Pathology and Molecular Immunology, University of Porto (IPATIMUP), 4200-465 Porto, Portugal
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Wang Y, Meeker AK, Kowalski J, Tsai HL, Somervell H, Heaphy C, Sangenario LE, Prasad N, Westra WH, Zeiger MA, Umbricht CB. Telomere length is related to alternative splice patterns of telomerase in thyroid tumors. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:1415-24. [PMID: 21763260 DOI: 10.1016/j.ajpath.2011.05.056] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 04/19/2011] [Accepted: 05/11/2011] [Indexed: 01/02/2023]
Abstract
Telomere dysfunction and aberrant telomerase expression play important roles in tumorigenesis. In thyroid tumors, three possibly inhibitory splice variants of the active full-length isoform of human telomerase reverse transcriptase (hTERT) may be expressed. These variants might regulate telomerase activity and telomere length because it is the fraction of the full-length isoform, rather than the total transcript level, that correlates with enzymatic activity. Telomerase reactivation may be critical in the early stages of tumorigenesis, when progressive telomere shortening may be limiting cell viability. The aim of this study was to investigate the relationship between telomere length and hTERT splice variant expression patterns in benign and well-differentiated malignant thyroid tumors. Telomere lengths of 61 thyroid tumors were examined by fluorescence in situ hybridization, comparing tumors with adjacent normal thyroid tissue on the same slide. Expression patterns of hTERT splice variants were evaluated by quantitative and nested RT-PCR. Telomere length was inversely correlated with percentage of full-length hTERT expression rather than with total hTERT expression levels. Short telomeres and high fractions of full-length hTERT transcripts were associated with follicular and papillary thyroid carcinomas, whereas long telomeres and low levels of full-length hTERT were associated with benign thyroid nodules. Intermediate levels of full-length hTERT and telomere length were found in follicular variant of papillary thyroid carcinomas and follicular adenomas.
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Affiliation(s)
- Yongchun Wang
- Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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Hiyama E, Hiyama K. Telomerase detection in the diagnosis and prognosis of cancer. Cytotechnology 2011; 45:61-74. [PMID: 19003244 DOI: 10.1007/s10616-004-5126-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2004] [Accepted: 09/21/2004] [Indexed: 01/27/2023] Open
Abstract
Telomerase, a critical enzyme responsible 'for cellular immortality, is usually repressed in somatic cells except for lymphocytes and self-renewal cells, but is activated in approximately 85% of human cancer tissues. The human telomerase reverse transcriptase (hTERT) is the catalytic component of human telomerase. In cancers in which telomerase activation occurs at the early stages of the disease, telomerase activity and hTERT expression are useful markers for the detection of cancer cells. In other cancers in which telomerase becomes upregulated upon tumor progression, they are useful as prognostic indicators. However, careful attention should be paid to false-negative results caused by the instability of telomerase and of the hTERT mRNA and the presence of PCR inhibitors, as well as to false-positive results caused by the presence of alternatively spliced hTERT mRNA and normal cells with telomerase activity. Recently, methods for the in situ detection of the hTERT mRNA and protein have been developed. These methods should facilitate the unequivocal detection of cancer cells, even in tissues containing a background of normal telomerase-positive cells.
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Affiliation(s)
- Eiso Hiyama
- Natural Science Center for Basic Research and Development, RIRBM, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan,
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Abstract
Although fine-needle aspiration biopsy (FNA) remains the mainstay of the preoperative workup of thyroid nodules, it does not provide a diagnosis in up to 20% of nodules. This group of indeterminate lesions, including lesions with cellular atypia, suspicious cytology, and demonstrating a follicular pattern, provides one of the greatest challenges to researchers in thyroid cancer today. Over the last 2 decades, considerable work has been done to find molecular markers to resolve this diagnostic dilemma. This article explores some of the markers including galectin-3, HBME-1, BRAF, RET/PTC, PAX8-PPARgamma, hTERT, telomerase, miRNA, and microarray and multigene assays. Although no one marker has proven to be a panacea, several combinations of markers have shown great promise as an adjunct to FNA.
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Affiliation(s)
- Meredith A Kato
- Division of Endocrine Surgery, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY 10068, USA.
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Capezzone M, Marchisotta S, Cantara S, Pacini F. Telomeres and thyroid cancer. Curr Genomics 2009; 10:526-533. [PMID: 20514214 PMCID: PMC2817883 DOI: 10.2174/138920209789503897] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Revised: 06/26/2009] [Accepted: 06/29/2009] [Indexed: 02/08/2023] Open
Abstract
Telomeres are specialized structures at the ends of chromosomes, consisting of hundreds of repeated hexanucleotides (TTAGGG)n. Genetic integrity is partly maintained by the architecture of telomeres and it is gradually lost as telomeres progressively shorten with each cell replication, due to incomplete lagging DNA strand synthesis and oxidative damage. Telomerase is a reverse transcriptase enzyme that counteracts telomere shortening by adding telomeric repeats to the G-rich strand. It is composed of a telomerase RNA component and a protein component, telomerase reverse transcriptase. In the absence of telomerase or when the activity of the enzyme is low compared to the replicative erosion, apoptosis is triggered. Patients who have inherited genetic defects in telomere maintenance seem to have an increased risk of developing familial benign diseases or malignant diseases. At the somatic level, telomerase is reactivated in the majority of human carcinomas, suggesting that telomerase reactivation is a critical step for cancerogenesis.In sporadic thyroid carcinoma telomerase activity is detectable in nearly 50% of thyroid cancer tissues and some authors proposed that the detection of telomerase activity may be used for differentiating between benign and malignant thyroid tumours. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial papillary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer.In this report, we will review the role of telomere-telomerase complex in sporadic and familial thyroid cancer.
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Affiliation(s)
| | | | | | - Furio Pacini
- Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, Section of Endocrinology and Metabolism, University of Siena, Siena, Italy
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Marchetti I, Lessi F, Mazzanti CM, Bertacca G, Elisei R, Coscio GD, Pinchera A, Bevilacqua G. A morpho-molecular diagnosis of papillary thyroid carcinoma: BRAF V600E detection as an important tool in preoperative evaluation of fine-needle aspirates. Thyroid 2009; 19:837-42. [PMID: 19534623 DOI: 10.1089/thy.2009.0074] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Although most thyroid nodule fine-needle aspiration (FNA) diagnoses are definitive or nearly definitive, about 30% of them are not read as definitively benign or malignant, the so-called indeterminate or suspicious FNA diagnosis. The prevalence of malignancy in FNA samples with these diagnoses varies from 10% to 52%. The first aim of this study was to determine if BRAF V600E analysis of thyroid FNA cytological smears could be performed with a relatively simple protocol. We also sought to determine if assessing the presence of BRAF gene mutations in preoperative FNA cytology slides would provide diagnostic information for FNA samples with a reading of indeterminate or suspicious thyroid lesions. METHODS DNA was extracted directly from FNA-stained smears of 111 patients with thyroid lesions having different cytological diagnoses. There was 1 cystic nodule, 20 microfollicular proliferations without atypia, 32 that were suspicious for papillary carcinoma, 56 papillary thyroid carcinomas (PTC), and 2 poorly differentiated carcinomas. The BRAF V600E mutational status was determined by sequencing analysis in all patients. The histopathological diagnosis was obtained in all cases. RESULTS We observed that 56/90 (62.3%) patients received a definitive diagnosis of PTC when only cytology was used. After molecular analysis, the BRAF V600E mutation was detected in 18/32 (56.2%) cases with a cytology of suspicious for papillary carcinoma and 41/56 (73.2%) with PTC. According to the morpho-molecular analysis (i.e., traditional cytology combined with BRAF V600E analysis) 74/90 (82.2%) patients could be assigned a definitive diagnosis of PTC. Therefore, the addition of molecular analysis yielded an increase of 20% in the sensitivity compared to cytology alone. CONCLUSIONS The method of molecular analysis of thyroid FNA smears described here can be easily performed after the FNA, thereby avoiding inconvenience and additional time during the FNA and permitting later analysis of samples having indeterminate cytology features. The increased sensitivity of this preoperative morpho-molecular analysis should provide information that is useful in deciding the extent of thyroid surgery for thyroid nodules that are indeterminate or suspicious on cytology.
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Affiliation(s)
- Ivo Marchetti
- University of Pisa and Pisa University Hospital, Italy.
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10
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Proctor A, Brownhill SC, Burchill SA. The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility. Biochim Biophys Acta Mol Basis Dis 2009; 1792:260-74. [PMID: 19264125 DOI: 10.1016/j.bbadis.2009.02.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 02/19/2009] [Accepted: 02/20/2009] [Indexed: 01/12/2023]
Abstract
The Ewing's sarcoma family of tumours (ESFT) are diagnosed by EWS-ETS gene translocations. The resulting fusion proteins play a role in both the initiation and maintenance of these solid aggressive malignant tumours, suppressing cellular senescence and increasing cell proliferation and survival. EWS-ETS fusion proteins have altered transcriptional activity, inducing expression of a number of different target genes including telomerase. Up-regulation of hTERT is most likely responsible for the high levels of telomerase activity in primary ESFT, although telomerase activity and expression of hTERT are not predictive of outcome. However levels of telomerase activity in peripheral blood may be useful to monitor response to some therapeutics. Despite high levels of telomerase activity, telomeres in ESFT are frequently shorter than those of matched normal cells. Uncertainty about the role that telomerase and regulators of its activity play in the maintenance of telomere length in normal and cancer cells, and lack of studies examining the relationship between telomerase activity, regulators of its activity and their clinical significance in patient samples have limited their introduction into clinical practice. Studies in clinical samples using standardised assays are critical to establish how telomerase and regulators of its activity might best be exploited for patient benefit.
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Affiliation(s)
- Andrew Proctor
- Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK
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Expression of cell cycle biomarkers and telomere length in papillary thyroid carcinoma: a comparative study between radiation-associated and spontaneous cancers. Am J Clin Oncol 2009; 32:1-8. [PMID: 19194115 DOI: 10.1097/coc.0b013e3181783336] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Radiation exposure during childhood is the only well-established risk factor for papillary thyroid carcinoma (PTC). To better define the biologic profile of radiation-induced and sporadic PTC, we compared in these two groups of PTC the expression of cell cycle regulatory proteins and telomere length. METHODS Cell cycle markers (cyclin A, B1, D1, E, and Ki67) were evaluated on 100 PTC specimens (26 radiation-induced and 74 sporadic PTCs). The expression of cell cycle regulators was studied using immunohistochemistry; telomere length heterogeneity was studied using in situ hybridization in a subset of 16 formalin-fixed samples (8 radiation-induced and 8 sporadic PTCs). RESULTS At multivariate analysis, only cytoplasmic cyclin E staining was overexpressed in sporadic cases (P = 0.006). The other cell cycle markers and telomere length did not differ significantly between sporadic PTC and radiation-induced PTC. CONCLUSIONS These markers cannot be used to differentiate radiation-induced from sporadic PTCs.
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Nagasaka A, Oda N, Nakai A, Hotta K, Nagata M, Kato T, Suzuki A, Itoh M, Miura H, Hakuta M, Yoshida S, Hibi Y, Iwase K. Thyroglobulin may affect telomerase activity in thyroid follicular cells. J Enzyme Inhib Med Chem 2008; 24:524-30. [PMID: 18830915 DOI: 10.1080/14756360802218920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Telomerase (TA) activity is known to be present in malignant tumor cells, but not in most somatic differentiated cells. TA shows relatively high activity in thyroid cancer cells, but reports vary. This fact prompted us to elucidate whether cell component inhibitors of TA in the thyroid follicles can modulate its activity. The activity of TA extracted from Hela cells was inhibited by mixing with the supernatant fraction of human thyroid tissue extract. To examine the effect of iodine, thyroid hormones (l-T3 and l-T4) and human thyroglobulin (hTg) contained in the thyroid follicles, l-T3, l-T4 and hTg were added to the TRAP assay system in vitro, using TA from Hela cells. Iodine, l-T3 and l-T4 did not affect TA activity, but hTg inhibited the TA activity in a dose-dependent manner (IC(50) of hTg: ca 0.45 microM: inhibiting concentration of hTg was from 0.15 microM to 3.0 microM). The hTg inhibition was not evident in the RT-PCR system, suggesting no effect of hTg on Taq DNA polymerase activity. The hTg inhibition of TA activity was attenuated by dNTP but not significantly by TS primer. These data suggest that hTg contained in thyroid follicular cells of various thyroid diseases may affect the TA activity measured in biopsied thyroid specimens, and that the reduction of the TA activity by hTg may induce slow progression and growth, and low grade malignancy of thyroid cancer, particularly differentiated carcinoma.
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Affiliation(s)
- Akio Nagasaka
- Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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Capezzone M, Cantara S, Marchisotta S, Filetti S, De Santi MM, Rossi B, Ronga G, Durante C, Pacini F. Short telomeres, telomerase reverse transcriptase gene amplification, and increased telomerase activity in the blood of familial papillary thyroid cancer patients. J Clin Endocrinol Metab 2008; 93:3950-3957. [PMID: 18664542 DOI: 10.1210/jc.2008-0372] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Differentiated papillary thyroid cancer is mostly sporadic, but the recurrence of the familial form has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer. OBJECTIVE The aim of our work was to study the telomere-telomerase complex in the peripheral blood of patients with familial papillary thyroid cancer (FPTC), including the measurement of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity, and search of hTERT or telomerase RNA component gene mutations. PATIENTS Cumulating a series of patients seen at the University of Siena and a series at the University of Rome, the experiments were conducted in 47 FPTC patients, 75 sporadic papillary thyroid cancer (PTC) patients, 20 patients with nodular goiter, 19 healthy subjects, and 20 unaffected siblings of FPTC patients. RESULTS RTL, measured by quantitative PCR, was significantly (P < 0.0001) shorter in the blood of FPTC patients, compared with sporadic PTCs, healthy subjects, nodular goiter subjects, and unaffected siblings. Also by fluorescence in situ hybridization analysis, the results confirmed shorter telomere lengths in FPTC patients (P = 0.01). hTERT gene amplification was significantly (P < 0.0001) higher in FPTC patients, compared with the other groups, and in particular, it was significantly (P = 0.03) greater in offspring with respect to parents. hTERT mRNA expression, as well as telomerase activity, was significantly higher (P = 0.0003 and P < 0.0001, respectively) in FPTC patients, compared with sporadic PTCs. RTL, measured in cancer tissues, was shorter (P < 0.0001) in FPTC patients, compared with sporadic PTCs. No mutations of the telomerase RNA component and hTERT genes were found. CONCLUSION Our study demonstrates that patients with FPTC display an imbalance of the telomere-telomerase complex in the peripheral blood, characterized by short telomeres, hTERT gene amplification, and expression. These features may be implicated in the inherited predisposition to develop FPTC.
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Affiliation(s)
- Marco Capezzone
- Department of Internal Medicine, University of Siena, Policlinico Santa Maria alle Scotte, 53100 Siena, Italy
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Low telomerase activity: possible role in the progression of human medullary thyroid carcinoma. Eur J Cancer 2008; 44:866-75. [PMID: 18296042 DOI: 10.1016/j.ejca.2007.12.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2007] [Revised: 12/17/2007] [Accepted: 12/20/2007] [Indexed: 11/22/2022]
Abstract
Maintenance of telomere length has been reported to be an absolute requirement for unlimited growth of human tumour cells and in about 85% of cases, this is achieved by reactivation of telomerase, the enzyme that elongates telomeres. Only in rare cases, like in human medullary thyroid carcinomas (MTC), telomerase activity (TA) is low or undetectable; however, this does not limit tumours to become clinically significant. Here, we report that very low TA (below 5% of HEK293) observed in MTC cell strains derived from different patients, although not sufficient for immortalising the cells, is necessary for prolonging their replicative life span. Telomere erosion led to induction of a crisis period after long-term in vitro cultivation, which was reached earlier when treating the cells with MST-312, a telomerase inhibitor at non-toxic concentrations. Crisis was bypassed either by ectopic hTERT introduction or by infrequent spontaneous immortalisation, the latter of which was always associated with telomerase reactivation and changes of the cellular phenotype. While confirming the high importance of telomerase for tumour development, these data draw attention to the relevance of low TA: although insufficient for telomere stabilisation, it allows MTC cells to reach more population doublings, increasing both cell numbers as well as the risk of accumulating mutations and thus might support the development of clinically significant MTC.
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15
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Frías C, García-Aranda C, De Juan C, Morán A, Ortega P, Gómez A, Hernando F, López-Asenjo JA, Torres AJ, Benito M, Iniesta P. Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer. Lung Cancer 2008; 60:416-25. [PMID: 18077053 DOI: 10.1016/j.lungcan.2007.11.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Revised: 11/02/2007] [Accepted: 11/02/2007] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND PURPOSE Telomere function and DNA damage response pathways are frequently inactivated in cancer. Moreover, some telomere-binding proteins have been implicated in DNA repair. The purpose of this work consists of evaluating the prognostic impact of telomere dysfunction and its relationship with DNA repair systems in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS We analysed 83 NSCLCs and their corresponding control samples obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. DNA repair expression assays were established by using cDNA arrays containing 96 DNA-repair genes and by Real Time Quantitative PCR. RESULTS Our data indicated that telomere attrition was significantly associated with poor clinical outcome of patients (P=0.02), being this parameter a significant prognostic factor independent of tumour stage (P=0.012; relative risk=1.887; 95% CI: 1.147-3.102). DNA-repair gene expression studies showed down regulation of DCLRE1C and GTF2H1 and a clear FLJ10858 up regulation in tumour tissues, as compared to controls. In addition, a number of genes related to DNA-repair were significantly down regulated in tumours that reactivated telomerase (DCLRE1C, GTF2H1, PARP-3, MLH1, and TRF2). CONCLUSIONS Telomere shortening emerged as a poor clinical evolution parameter in NSCLC. Moreover, results from this work suggest a relationship between the loss of several DNA repair genes and telomerase activity, which may be of relevance in the pathogenesis of non-small lung cancer.
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Affiliation(s)
- Cristina Frías
- Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain
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16
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Johnson JE, Gettings EJ, Schwalm J, Pei J, Testa JR, Litwin S, von Mehren M, Broccoli D. Whole-genome profiling in liposarcomas reveals genetic alterations common to specific telomere maintenance mechanisms. Cancer Res 2007; 67:9221-8. [PMID: 17909028 DOI: 10.1158/0008-5472.can-07-1133] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Telomere attrition ultimately leads to the activation of protective cellular responses, such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we use a liposarcoma model system to assay telomere maintenance mechanism (TMM)-specific genetic alterations. A multiassay approach was used to assess the TMMs active in tumors. Genomic DNA from these samples was then analyzed by high-resolution DNA mapping array to identify genetic alterations. Our data reveal a higher level of genome instability in alternative lengthening of telomere (ALT)-positive tumors compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance used. We also identified genetic changes specific to the ALT mechanism (e.g., deletion of chromosome 1q32.2-q44) as well as changes that are underrepresented among ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention.
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Affiliation(s)
- Jay E Johnson
- Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404, USA
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17
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Abstract
PURPOSE OF REVIEW To examine the activation of telomere maintenance in a variety of sarcoma subtypes, and to review the consequences of telomere maintenance with respect to genome stability and tumor progression. RECENT FINDINGS A hallmark of tumor cells is replicative immortality, which can be achieved, in part, by the activation of a telomere maintenance mechanism. A significant proportion of tumors show activation of telomerase, a specialized enzyme that adds telomeric repeats to pre-existing telomeres. Recent work has demonstrated, however, that a telomerase-independent mechanism called ALT (alternative lengthening of telomeres) is activated as frequently as telomerase in a variety of tumor types, particularly those of mesenchymal origin. Accordingly, panels of mesenchymal tumors have been interrogated for telomere maintenance mechanism, as well as characteristics such as tumor grade and patient survival. SUMMARY These studies indicate a strong positive correlation between the activation of a telomere maintenance mechanism and tumor progression in sarcomas. In addition, the activation of either ALT or telomerase is correlated with poorer patient prognosis as compared with a lack of telomere maintenance. Ongoing studies aimed at elucidating the roles of ALT and telomerase in tumorigenesis should ultimately allow for the development of strategies to improve treatment of these malignancies.
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Affiliation(s)
- Jay E Johnson
- Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404, USA
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18
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Matsuo T, Hiyama E, Sugita T, Shimose S, Kubo T, Mochizuki Y, Adachi N, Kojima K, Sharman P, Ochi M. Telomerase Activity in Giant Cell Tumors of Bone. Ann Surg Oncol 2007; 14:2896-902. [PMID: 17653593 DOI: 10.1245/s10434-007-9391-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Accepted: 01/04/2006] [Indexed: 11/18/2022]
Abstract
BACKGROUND A giant cell tumor of bone (GCT) is a histologically benign neoplasma that has an unpredictable pattern of biological aggressiveness. In the present study, we investigated whether there was a correlation between telomere length or the levels of telomerase activity and other clinical features of GCTs, for the possible use of these factors as parameters of aggressiveness or prognosis. METHODS In 16 surgically resected GCTs specimens, telomere length was assessed by terminal restriction fragments by Southern blot analysis. Telomerase activity was measured by a semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol assay. RESULTS Telomere length reduction was observed in 69% of the GCT samples. The telomere lengths of tumors were significantly shorter than those of normal tissue (P = .008). The mean telomere length of grade 3 tumors was significantly shorter than those of grade 1 and 2 tumors (P = .038). Telomerase activity was detected in 81% of tumor samples. The level of telomerase activity in tumors with local recurrence was significantly higher than in tumors without local recurrence (P = .011). CONCLUSIONS These results suggest that telomere length correlates with roentgenographic grade as a result of the frequency of cell division, and high telomerase activity indicates the aggressiveness of GCTs.
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Affiliation(s)
- Toshihiro Matsuo
- Department of Orthopaedic Surgery, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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19
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Rowe LR, Bentz BG, Bentz JS. Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules. Cytojournal 2006; 3:10. [PMID: 16606457 PMCID: PMC1481512 DOI: 10.1186/1742-6413-3-10] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2005] [Accepted: 04/10/2006] [Indexed: 11/13/2022] Open
Abstract
Background Fine needle aspiration (FNA) is widely utilized for evaluation of patients with thyroid nodules. However, approximately 30% are indeterminate for malignancy. Recently, a mutation in the BRAF gene has been reported to be the most common genetic event in papillary thyroid carcinoma (PTC). In this retrospective study, we assessed the utility of BRAF V600E mutation detection for refining indeterminate preoperative cytologic diagnoses in patients with PTC. Methods Archival indeterminate thyroid FNAs and corresponding formalin-fixed, paraffin-embedded (FFPE) surgical samples with PTC were identified in our patient files. DNA extracted from slide scape lysates and 5 μm FFPE sections were evaluated for the BRAF V600E mutation using LightCycler PCR and fluorescent melting curve analysis (LCPCR). Amplification products that showed deviation from the wild-type genomic DNA melting peak, discordant FNA and FFPE matched pairs, and all benign control samples, underwent direct DNA sequencing. Results A total of 19 indeterminate thyroid FNAs demonstrating PTC on FFPE surgical samples were included in the study. Using BRAF mutation analysis, the preoperative diagnosis of PTC was confirmed in 3/19 (15.8%) FNA samples that could not be conclusively diagnosed on cytology alone. However, 9/19 (47.4%) FFPE tissue samples were positive for the V600E mutation. Of the discordant pairs, 5/6 FNAs contained less than 50% tumor cells. Conclusion When used with indeterminate FNA samples, BRAF mutation analysis may be a useful adjunct technique for confirming the diagnosis of malignancy in an otherwise equivocal case. However, overall tumor cell content of some archival FNA smear slides is a limiting factor for mutation detection.
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Affiliation(s)
- Leslie R Rowe
- Institute for Clinical and Experimental Pathology, Associated Regional and University Pathologists (ARUP) Laboratories, Salt Lake City, UT, USA
| | - Brandon G Bentz
- Division of Otolaryngology, Department of Surgery, University of Utah, Salt Lake City, UT, USA
| | - Joel S Bentz
- Institute for Clinical and Experimental Pathology, Associated Regional and University Pathologists (ARUP) Laboratories, Salt Lake City, UT, USA
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
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20
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Garcia-Aranda C, de Juan C, Diaz-Lopez A, Sanchez-Pernaute A, Torres AJ, Diaz-Rubio E, Balibrea JL, Benito M, Iniesta P. Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma. Cancer 2006; 106:541-51. [PMID: 16388518 DOI: 10.1002/cncr.21625] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Telomere maintenance has been proposed as an essential step for tumor cell immortalization. The objectives of the current study were to investigate the mechanisms implicated in telomere length in colorectal carcinoma (CRC) and to evaluate the prognostic impact of telomere status. METHODS Ninety-one colorectal carcinoma samples that were obtained from patients who underwent surgery were analyzed to investigate the factors related to telomere function. The authors studied telomerase activity, terminal restriction fragment (TRF) length, and telomeric-repeat binding factor (TRF1) expression and analyzed the prognostic implications of those factors. RESULTS Most tumors (81.3%) displayed telomerase activity. Overall, telomeres in CRC specimens were significantly shorter compared with telomeres in normal, adjacent specimens (P=0.02). Moreover, tumors that demonstrated shortened telomeres displayed higher TRF1 levels than tumors without telomere shortening. In relation to patient prognosis, a significantly poor clinical course was observed in the group of patients who had tumors with longer telomeres (P=0.02), and this finding emerged as an independent prognostic factor in a Cox proportional hazards model (P=0.04; relative risk, 6.48). Among patients with tumors classified as telomerase-positive, telomere length ratios (the ratio of tumor tissues to normal tissues)<or=0.66 or TRF1 over-expression conferred a favorable outcome (P=0.03 and P=0.05, respectively). CONCLUSIONS The majority of CRC specimens in the current study displayed telomerase reactivation. However, only those tumors that displayed telomere elongation conferred a poor prognosis. Conversely, colorectal tumors that over-expressed TRF1 demonstrated telomere shortening, and patients with those tumors had a better clinical course.
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Affiliation(s)
- Cristina Garcia-Aranda
- Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
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21
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Jin YL, Yue W, Shi GX, Liu Y, Zhao FT, Zhu LP. Inhibition of 6A8 alpha-mannosidase gene expression resulted in telomere length shortening in nasopharyngeal carcinoma cell CNE-2L2. Cancer Lett 2005; 218:229-34. [PMID: 15670901 DOI: 10.1016/j.canlet.2004.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2003] [Revised: 03/06/2004] [Accepted: 04/16/2004] [Indexed: 11/22/2022]
Abstract
Telomere length shortening was observed in the nasopharyngeal carcinoma cell CNE-2L2 when 6A8 alpha-mannosidase expression was inhibited by antisense 6A8 DNA. Transduction with mock or an irrelevant DNA did not affect the telomere length in the carcinoma cells. Telomerase activity and mRNA transcription of TRF 1 and 2 were not changed in the cells treated with antisense 6A8. The Con A binding test showed an enhancement on the proteins isolated from the cells treated with antisense 6A8, but not on those from mock- or irrelevant DNA-treated cells. The data imply an association between glycosylation modification with telomere shortening in antisense 6A8-treated cells.
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Affiliation(s)
- Y L Jin
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
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22
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Wang SL, Chen WT, Wu MT, Chan HM, Yang SF, Chai CY. Expression of human telomerase reverse transcriptase in thyroid follicular neoplasms: an immunohistochemical study. Endocr Pathol 2005; 16:211-8. [PMID: 16299404 DOI: 10.1385/ep:16:3:211] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Differential diagnosis of follicular adenoma (FA) and follicular carcinoma (FC) of the thyroid can be difficult in the routine practice of surgical pathology because the diagnosis of FC is strictly defined and determined by the presence of capsular and/or vascular invasion by the tumor. These features may be equivocal in the histologic sections. On the other hand, telomerase is expressed in many human cancers and is thought to contribute to their immortality. Human telomerase reverse transcriptase (hTERT) is the major determinant of human telomerase activity, and its expression is suggestive of capacity for unlimited replication. This case-control study examined the expression of hTERT using immunohistochemistry in 36 thyroid FC and 36 FA from patients who were matched by age and sex. The aim was to investigate the value of immunohistochemical staining for hTERT in the differential diagnosis of follicular neoplasms. The results revealed 23 cases of FC and 14 cases of FA that showed high expression of hTERT, with moderate to strong immunoreactivity. The remaining cases showed weak or negative staining. The difference between FA and FC was statistically significant (p < 0.05). In conclusion, immunohistochemical staining for hTERT can be considered an ancillary marker for differential diagnosis of FA and FC.
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Affiliation(s)
- Sheng-Lan Wang
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
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23
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Ulaner GA, Hoffman AR, Otero J, Huang HY, Zhao Z, Mazumdar M, Gorlick R, Meyers P, Healey JH, Ladanyi M. Divergent patterns of telomere maintenance mechanisms among human sarcomas: sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing's sarcomas and osteosarcomas. Genes Chromosomes Cancer 2004; 41:155-62. [PMID: 15287028 DOI: 10.1002/gcc.20074] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Two types of telomere maintenance mechanisms (TMMs) have been described in human tumors: telomerase activation and alternative lengthening of telomeres (ALT). Although the vast majority of epithelial tumors rely on telomerase activation, many mesenchymal tumors rely on ALT for telomere maintenance, but within this tumor group, the TMMs used by translocation-associated sarcomas have not been systematically studied. We studied telomere lengths and telomerase expression and activity in 30 uncultured tumor samples and in 10 cell lines of Ewing's sarcoma, a prototypical translocation-associated sarcoma, and compared the data to an identical analysis of 60 osteosarcomas, the most common type of sarcoma lacking a specific translocation. Telomerase activity was demonstrated in 21 Ewing's sarcoma tumor samples (70%) and in 9 of 10 Ewing's sarcoma cell lines. Evidence of ALT, indicated by the presence of long and heterogeneous telomeres, was observed only in the cell line without telomerase activity and in none of the 30 Ewing's sarcoma tumor samples. The 9 Ewing's sarcoma patients whose tumors lacked detectable telomerase activity did not differ significantly from the remaining patients in age, stage, EWSR1-FLI1 fusion type, prevalence of TP53 point mutations, or overall survival. The low prevalence of ALT in Ewing's sarcoma contrasted sharply with our data on TMMs in 60 osteosarcomas, which showed ALT in 38 of 60 cases (P<0.0001). The present study, together with emerging published data on other sarcoma types, suggests that a predominance of telomerase activation in the absence of ALT may characterize sarcomas with specific chromosomal translocations (such as Ewing's sarcoma), whereas a high prevalence of ALT appears typical of sarcomas with nonspecific complex karyotypes (such as osteosarcoma).
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Affiliation(s)
- Gary A Ulaner
- Medical Service, VA Palo Alto Health Care System, and Department of Medicine, Stanford University, Palo Alto, California 94304, USA.
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Abstract
Telomere shortening limits the proliferative capacity of primary human cells and restrains the regenerative capacity of organ systems during chronic diseases and aging. Telomere shortening apparently has a dual role in tumor development and progression. On the one hand, it induces chromosomal instability and the initiation of cancer; on the other hand, tumor progression requires stabilization of telomeres. The predominant mechanism of telomere stabilization in tumor cells is the activation of the telomere-synthesizing enzyme telomerase. The potential use of telomerase activators for the treatment of regenerative disorders will ultimately depend on their effects on tumorigenesis. This review focuses on the role of telomere shortening and telomerase in carcinogenesis with a special focus on hepatocellular carcinoma.
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Affiliation(s)
- Ande Satyanarayana
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany
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25
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Han R. [Current opinion on the etiology of differentiated thyroid carcinoma]. ACTA CHIRURGICA IUGOSLAVICA 2004; 50:51-5. [PMID: 15179755 DOI: 10.2298/aci0303051h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
It is apparent that in the last decade carcinoma of the thyroid is becoming increasingly prevalent. The multistage complex theory of thyroid carcinogenesis is based on observations made on cohort patients studies and during animal experiments over a period of last fifty years. The process of thyroid oncogenesis is conceived to be a series of events induced by genetic and environmental factors which alter follicular cells division and growth control. These factors can be considered as initiators (chemical agents and ionising radiation) and promoters (some goitrogenes and drugs). The first class of factors induce incipient tumorigenesis while the second augments TSH secretion and radically increases tumour growth. Normally silent, intracellular proto-oncogenes (of which Ret/PTC series are the most conceived ones) can become activated by chromosomal translocations, deletions or mutations and can transform normal follicular cell into a condition of uncontrolled division and growth. The most significant known cause of thyroid carcinomas in men is exposure to external or internal ionising radiation. Beside that, long-term iodine deficiency, effects of certain chemical carcinogens, drugs and goitrogenes must be considered as significant risk factors. Possible role of sodium/iodide symporter is becoming an objective of the most recent investigations.
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Affiliation(s)
- R Han
- Institut za nuklearnu medicinu, KCS, Beograd
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Preto A, Singhrao SK, Haughton MF, Kipling D, Wynford-Thomas D, Jones CJ. Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: implications for antitelomerase therapy. Oncogene 2004; 23:4136-45. [PMID: 15064743 DOI: 10.1038/sj.onc.1207564] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Telomerase activity in tumours is often associated with p53 mutation. Many antitelomerase therapies take advantage of the inability of cells expressing mutant p53 to undergo replicative senescence, since this allows telomere erosion to continue until 'crisis', hence providing the desired cytotoxic effect. However, some tumour types, including breast, melanomas and thyroid, retain wild-type p53 function and the effectiveness of antitelomerase therapies in such tumour cells have not been adequately addressed. To explore this, we made use of two thyroid cancer cell lines K1 and K2, which retain wt p53. Telomere erosion induced by the expression of a dominant-negative (DN) hTERT resulted in delayed onset of growth arrest in K1 and K2 cells, reminiscent of replicative senescence, with low levels of BrdU labelling and apoptosis, associated with high p21(WAF1) and senescence-associated beta galactosidase expression. In contrast, abrogation of p53 function by the expression of HPV16 E6 in K1 and K2 cells either at the same time as DNhTERT or just prior to the onset of senescence allowed cells to continue growing until 'crisis'. Likewise, microinjection of a p53 neutralizing antibody into 'senescent' K1 DNhTERT cells permitted re-entry into the cell cycle. We conclude that thyroid tumour cells with wild-type p53 retain an intact p53-mediated growth arrest response to telomere erosion. This raises the intriguing question of why, therefore, p53 mutation is not selected for in such cancers, and also calls into question the therapeutic value of telomerase inhibitors in such cases.
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Affiliation(s)
- Ana Preto
- Institute of Molecular Pathology and Immunology of the University of Porto, (IPATIMUP), Rua Dr Roberto Frias, s/n, 4200-465 Porto, Portugal
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Karayan-Tapon L, Menet E, Guilhot J, Levillain P, Larsen CJ, Kraimps JL. Topoisomerase II alpha and telomerase expression in papillary thyroid carcinomas. Eur J Surg Oncol 2004; 30:73-9. [PMID: 14736527 DOI: 10.1016/j.ejso.2003.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Altered topoisomerase II alpha (Topo II alpha) expression and telomerase activity (TA) reflect tumour cell growth and malignant transformation. METHODS We examined TA by using a TRAP assay and expression of Topo II alpha by immunohistochemical analysis in a series of 27 cases of papillary thyroid carcinoma (PTC). RESULTS Topo II alpha labelling index (LI) ranged from 0.1 to 4.2% and was significantly associated with patient age (r=-0.42, p=0.003), with higher levels of Topo II alpha in patients under 40 years. There was no relationship between Topo II alpha LI, AGES score or other clinical outcome. TA was detected in 14 PTC, with relative levels ranging from 1.2 to 102 units. A significant positive correlation between the multiplicity of tumoral foci and the TA levels (p<10(-2)) was noted. CONCLUSION We concluded that Topo II alpha cannot be used as a marker of tumour aggressiveness. Furthermore, enhanced Topo II alpha expression in PTCs from patients less than 40 years old suggests that this age group might benefit from Topo II inhibitor chemotherapy.
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Affiliation(s)
- L Karayan-Tapon
- Laboratoire de Protéines et Inflammation, CHU la Milétrie, 86021 Poitiers Cedex, France
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Affiliation(s)
- Evan Y Yu
- Dana-Farber Cancer Institute and Brigham and Women Hospital, Harvard Medical School, Boston, MA 02115, USA
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29
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Affiliation(s)
- Martin Schlumberger
- Service de Medecine Nucleaire, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France
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30
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Bravo SB, Pampín S, Cameselle-Teijeiro J, Carneiro C, Domínguez F, Barreiro F, Alvarez CV. TGF-β-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-κB activation. Oncogene 2003; 22:7819-30. [PMID: 14586408 DOI: 10.1038/sj.onc.1207029] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Millions of people worldwide suffer goiter, a proliferative disease of the follicular cells of the thyroid that may become neoplastic. Thyroid neoplasms have low proliferative index, low apoptotic index and a high incidence of metastasis. TGF-beta is overexpressed in thyroid follicular tumor cells. To investigate the role of TGF-beta in thyroid tumor progression, we established cultures of human thyrocytes from different proliferative pathologies (Grave's disease, multinodular goiter, follicular adenoma, papillary carcinoma), lymph node metastasis, and a normal thyroid sample. All cultures maintained the thyrocyte phenotype. TGF-beta induced cell-cycle arrest in all cultures, in contrast with results reported for other epithelial tumors. In deprived medium, TGF-beta induced apoptosis in normal thyrocyte cultures and all neoplastic cultures except the metastatic cultures. This apoptosis was mediated by a reduction in p27kip1 levels, inducing cell-cycle initiation. Antisense p27 expression induced apoptosis in the absence of TGF-beta. By contrast, in cells in which p27 was overexpressed, TGF-beta had a survival effect. In growth medium, a net survival effect occurs in neoplastic thyrocytes only, not normal thyrocytes, due to activation of the NF-kappaB survival program. Together, these findings suggest that (a) thyroid neoplasms are due to reduced apoptosis, not increased division, in line with the low proliferative index of these pathologies, and (b) TGF-beta induces apoptosis in normal thyrocytes via p27 reduction, but that in neoplastic thyrocytes this effect is overridden by activation of the NF-kappaB program.
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Affiliation(s)
- Susana B Bravo
- Department of Physiology, School of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
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Piao YF, Shi Y, Gao PJ. Inhibitory effect of all-trans retinoic acid on human hepatocellular carcinoma cell proliferation. World J Gastroenterol 2003; 9:2117-20. [PMID: 12970919 PMCID: PMC4656687 DOI: 10.3748/wjg.v9.i9.2117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the inhibitory effect of all-trans retinoic acid on human hepatocellular carcinoma cell line SMMC-7721 and to explore the mechanism of its effect.
METHODS: SMMC-7721 cells were divided into two groups, one treated with all-trans retinoic acid (ATRA) for 5 days and the other as a control group. Light microscope and electron microscope were used to observe the morphological changes. Telomerase activity was analyzed with silver-stained telomere repeated assay protocal (TRAP). Expression of Caspase-3 was demonstrated with western blot.
RESULTS: ATRA-treated cells showed differentiation features including small and pyknotic nuclei, densely stained chromatin and fewer microvilli. Besides, ATRA could inhibit the activity of telomerase, promote the expression of Caspase-3 and its activation.
CONCLUSION: Telomerase activity and Caspase-3 expression are changed in human hepatocellular carcinoma cell line SMMC-7721 treated with all-trans retinioc acid. The inhibition of telomerase activity and the activation of Caspase-3 may be the key steps through which ATRA inhibits the proliferation of SMMC-7721 cell line.
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Affiliation(s)
- Yun-Feng Piao
- Department of Gastroenterology, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
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Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC. Telomerase maintains telomere structure in normal human cells. Cell 2003; 114:241-53. [PMID: 12887925 DOI: 10.1016/s0092-8674(03)00550-6] [Citation(s) in RCA: 546] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In normal human cells, telomeres shorten with successive rounds of cell division, and immortalization correlates with stabilization of telomere length. These observations suggest that human cancer cells achieve immortalization in large part through the illegitimate activation of telomerase expression. Here, we demonstrate that the rate-limiting telomerase catalytic subunit hTERT is expressed in cycling primary presenescent human fibroblasts, previously believed to lack hTERT expression and telomerase activity. Disruption of telomerase activity in normal human cells slows cell proliferation, restricts cell lifespan, and alters the maintenance of the 3' single-stranded telomeric overhang without changing the rate of overall telomere shortening. Together, these observations support the view that telomerase and telomere structure are dynamically regulated in normal human cells and that telomere length alone is unlikely to trigger entry into replicative senescence.
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Affiliation(s)
- Kenkichi Masutomi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
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Trulsson LM, Velin AK, Herder A, Söderkvist P, Rüter A, Smeds S. Telomerase activity in surgical specimens and fine-needle aspiration biopsies from hyperplastic and neoplastic human thyroid tissues. Am J Surg 2003; 186:83-8. [PMID: 12842757 DOI: 10.1016/s0002-9610(03)00119-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Telomerase activity (TA) indicates malignancy, but activated lymphocytes also express TA. Correlation between TA in thyroid tissues and fine-needle aspiration (FNA) samples and knowledge about TA in adjacent tissue are of importance. METHODS The telomeric repeat amplification protocol assay followed by enzyme-linked immunosorbent assay detection was performed on 78 thyroid cases including 53 suspected malignancies, preoperative and perioperative FNA specimens, and adjacent tissue. RESULTS Benign lesions in cancer-suspected cases were TA negative. Eight of 13 papillary (62%) and 4 of 5 follicular (80%) tumors were TA positive (TA+). Lower TA was observed in conventional papillary cancer than in follicular, tall cell variant of papillary and anaplastic cancers. Adjacent tissues with lymphocyte infiltration were TA+ in 9 of 17 cases (53%). Nine of 65 adjacent tissues (14%) were TA+. Three of 6 preoperative and 9 of 11 perioperative FNA samples from malignant tumors corresponded to the tissue TA. CONCLUSIONS; High TA may reflect more severe thyroid cancer. Telomerase activity in FNA biopsies does not add reliable diagnostic information, and presence of lymphocytes can give false-positive results.
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Affiliation(s)
- Lena M Trulsson
- Division of Surgery, Department of Biomedicine and Surgery, Faculty of Health Sciences, University Hospital, SE-581 85 Linköping, Sweden
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Abstract
Telomerase, a critical enzyme responsible for continuous cell growth, is repressed in most somatic cells except proliferating progenitor cells and activated lymphocytes, and activated in approximately 85% of human cancer tissues. Telomerase activity is a useful cancer-cell detecting marker in some types of cancers in which almost all cases show telomerase activation. In other types in which telomerase becomes upregulated according to tumor progression, it is a useful prognostic indicator. Detection of human telomerase reverse transcriptase (hTERT) mRNA or protein in various clinical samples is also applicable. However, careful attention should be paid to the false negative results due to the instability of this enzyme or hTERT mRNA and the existence of polymerase chain reaction inhibitors as well as the false-positive results due to the contamination by normal cells with telomerase activity. If these pitfalls are avoided, in situ detection of hTERT mRNA or protein will facilitate the reliability of telomerase as a tumor marker.
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Abstract
Specialized nucleoprotein structures, termed telomeres, cap the ends of human chromosomes. These terminal structures, composed of repetitive arrays of guanine-rich hexameric DNA together with specific telomere-binding proteins, play essential roles in protecting the chromosome from damage and degradation. In addition, several lines of evidence implicate telomere maintenance as an important regulator of cell life span. Activation of telomerase, a dedicated reverse transcriptase that synthesizes telomeric sequences, is strongly associated with cancer, and recent observations confirm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation. These dual functions of telomere biology are evident in the clinical manifestations of the multisystem syndrome, dyskeratosis congenita, forms of which display defects in telomerase function. Recent advances in our understanding of telomere biology indicate that the manipulation of telomeres and telomerase will lead to clinically significant applications in the diagnosis, prevention, and treatment of neoplastic disease.
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Affiliation(s)
- William C Hahn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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36
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Abstract
The unique biology of telomeres and telomerase plays important roles in many aspects of mammalian cell physiology. Over the past decade, several lines of evidence have confirmed that the maintenance of telomeres and telomerase participate actively in the pathogenesis of human cancer. Specifically, activation of telomerase is strongly associated with cancer, and recent observations confirm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation by regulating genomic stability and cell lifespan. In addition, recent evidence suggests that telomerase activation contributes to tumorigenesis independently of its role in maintaining telomere length. Here we review recent developments in our understanding of the relationships among telomeres, telomerase, and cancer.
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Affiliation(s)
- Kenkichi Masutomi
- Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Dana 710C, Boston, MA 02115, USA
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37
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Bornstein-Quevedo L, García-Hernández ML, Camacho-Arroyo I, Herrera MF, Angeles AA, Treviño OG, Gamboa-Domínguez A. Telomerase activity in well-differentiated papillary thyroid carcinoma correlates with advanced clinical stage of the disease. Endocr Pathol 2003; 14:213-19. [PMID: 14586066 DOI: 10.1007/s12022-003-0013-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Clinical relevance and stage correlation of telomerase activity in well-differentiated papillary thyroid carcinoma (WD PTC) has not been well determined, as its reported activity could be due to the analysis of tumors with lymphocytic infiltrates or aggressive variants of papillary carcinomas. We conducted a prospective study of telomerase activity in WD PTC without inflammatory infiltrates and correlated it with clinical stage. Fifty WD PTCs were analyzed for telomerase activity by PCR-based TRAP (telomeric repeat amplification protocol) assay. Results were correlated with stage and other clinicopathologic variables. Twenty-one (42%) WD PTCs demonstrated telomerase activity. The enzyme was detected more frequently in stage III/IVa WD PTCs (p = 0.02) and in tumors with extra thyroidal extension (p = 0.04). The risk of presenting advanced disease (stage III/IVa) and extrathyroidal growth was significantly increased in telomerase-positive tumors (p = 0.01; odds ratio [OR] 4.4 [95%CI 1.3-14.7]) and (p = 0.04; OR 3.6 [95%CI 1.1-11.7]), respectively. Also, a correlation was found between telomerase activity and age. There was no correlation of telomerase activity with gender, histologic variant, tumor size, or cervical lymph node metastasis. Telomerase activity was observed in 42% of WD PTC and was detected more frequently in AJCC TNM stage III/IVa cases. This finding suggests that telomerase deregulation could be involved in tumor progression.
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Abstract
This review will focus on the clinical utilities of telomerase for human cancer diagnosis. Much attention has been focused on detection of telomerase activity and its essential components (hTR and hTERT) in cancer and noncancerous tissues. Expression of hTR and hTERT is upregulated in almost all human malignant tumors but not in benign or normal tissues with the exception of germline cells, proliferative stem cells, activated lymphocytes, and certain benign tumors. Thus, telomerase is a useful marker for cancer diagnosis and in some instance as a prognostic indicator of outcome. Telomerase detection in cells derived from breast fine needle aspirates, bronchial washes, and pancreatic juices show high sensitivity and specificity for cancer detection. In tissue samples, the level of telomerase activity is a useful prognostic indicator in certain adult cancers such as gastric and colon cancers and in neuroblastomas. Immunohistochemical detection of hTERT will facilitate exact diagnosis of the telomerase positive cells and expand the application of telomerase in cancer diagnosis.
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Affiliation(s)
- Eiso Hiyama
- Department of General Medicine, Hiroshima University, Faculty of Medicine, School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Hiroshima, Japan.
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Henson JD, Neumann AA, Yeager TR, Reddel RR. Alternative lengthening of telomeres in mammalian cells. Oncogene 2002; 21:598-610. [PMID: 11850785 DOI: 10.1038/sj.onc.1205058] [Citation(s) in RCA: 472] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Some immortalized mammalian cell lines and tumors maintain or increase the overall length of their telomeres in the absence of telomerase activity by one or more mechanisms referred to as alternative lengthening of telomeres (ALT). Characteristics of human ALT cells include great heterogeneity of telomere size (ranging from undetectable to abnormally long) within individual cells, and ALT-associated PML bodies (APBs) that contain extrachromosomal telomeric DNA, telomere-specific binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidentified. Repressors of ALT activity are present in normal cells and some telomerase-positive cells. Telomere length dynamics in ALT cells suggest a recombinational mechanism. Inter-telomeric copying occurs, consistent with a mechanism in which single-stranded DNA at one telomere terminus invades another telomere and uses it as a copy template resulting in net increase in telomeric sequence. It is possible that t-loops, linear and/or circular extrachromosomal telomeric DNA, and the proteins found in APBs, may be involved in the mechanism. ALT and telomerase activity can co-exist within cultured cells, and within tumors. The existence of ALT adds some complexity to proposed uses of telomere-related parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.
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Affiliation(s)
- Jeremy D Henson
- Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, Sydney 2145, Australia
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40
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Abstract
In 1994 a sensitive method for the detection of telomerase was described. This assay, which was based on the polymerase chain reaction, suggested that telomerase activity was associated with immortal and cancer cells. Since then more than a thousand studies have documented the expression and activity of the enzyme in diseased tissues, primarily tumours. This review gives an overview of the biological significance of telomerase expression and methods for detecting its activity. This is followed by an organ system-based discussion of expression in normal tissues and disease states. We finish with speculation as to the future role of telomerase detection in diagnostic histopathology.
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Affiliation(s)
- P Matthews
- Department of Pathology, University of Wales College of Medicine, Cardiff, UK.
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