The potential utility of telomere-related markers for cancer diagnosis. J Cell Mol Med

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 02/2011; 15(6):1227-38. DOI: 10.1111/j.1582-4934.2011.01284.x
Source: PubMed


The role telomeres and telomerase play in the initiation and progression of human cancers has been extensively evaluated. Telomeres are nucleoprotein complexes comprising the hexanucleotide DNA repeat sequence, TTAGGG and numerous telomere-associated proteins, including the six member Shelterin complex. The main function of the telomere is to stabilize the ends of the chromosomes. However, through multiple mechanisms, telomeres can become dysfunctional, which may drive genomic instability leading to the development of cancer. The majority of human cancers maintain, or actively lengthen, telomeres through up-regulation of the reverse transcriptase telomerase. Because there are significant differences in telomere length and telomerase activity between malignant and non-malignant tissues, many investigations have assessed the potential to utilize these molecular markers for cancer diagnosis. Here, we critically evaluate whether measurements of telomere lengths and telomerase levels may be clinically utilized as diagnostic markers in solid tumours, with emphasis on breast and prostate cancer as representative examples. Future directions focusing on the direct detection of dysfunctional telomeres are explored. New markers for telomere dysfunction may eventually prove clinically useful.

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Available from: Christopher Heaphy, Nov 14, 2014
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    • "Telomerase is active in many types of human cancers but is not detectable in most normal somatic cells (10,11). Therefore telomerase activity may be a universal and specific marker for diagnosing a wide variety of cancers (12). Several studies have shown that the measurement of telomerase activity may be a useful and noninvasive method to detect malignancy in body fluid, particularly when used in combination with conventional cytological examination (13,14). "
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    ABSTRACT: The telomerase activity assay has been established for the detection of malignant pleural effusion (MPE), however, the overall diagnostic accuracy of the telomerase activity assay for MPE remains unclear. We performed a systematic search in the Pubmed, Embase and Cochrane databases to identify published studies that have evaluated the diagnostic role of the telomerase activity assay for MPE. Sensitivity, specificity and other measures of accuracy of the telomerase activity assay in the diagnosis of MPE were pooled using the random effects models. A summary receiver operating characteristic (SROC) curve was used to summarize overall test performance. A total of eight studies met the inclusion criteria for the meta-analysis. The pooled sensitivity and specificity for diagnosing MPE were 0.76 [95% confidence intervals (CI), 0.72-0.80] and 0.87 (95% CI, 0.83-0.91), respectively. The positive likelihood ratio was 5.19 (95% CI, 2.36-11.42), the negative likelihood ratio was 0.25 (95% CI, 0.11-0.53) and the diagnostic odds ratio was 23.18 (95% CI, 6.11-87.83). The area under the SROC curve was 0.92. The telomerase activity assay plays a role in the diagnosis of MPE with a relatively high specificity. The results of a telomerase activity assay should be interpreted together with the combination of other test results and clinical findings.
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    • "The first report demonstrating telomerase as a prognostic marker in human malignancies was published on childhood neuroblastoma [11]. The question of whether telomerase and telomere dysfunction are useful prognostic markers is still debated [12] [13]. Glioblastoma multiforme (GBM, grade 4 astrocytoma) has a poor prognosis, with a median survival less than 2 years despite multimodality therapy [14]. "
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    ABSTRACT: Cancer cells bypass replicative senescence, the major barrier to tumor progression, by using telomerase or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms (TMMs). Correlation between ALT and patient survival was demonstrated for high-grade astrocytomas. Transcription from subtelomeres produces telomeric repeat-containing RNA (TERRA), a natural inhibitor of telomerase activity (TA). This led us to evaluate correlations of TERRA and TMM with tumor grade and outcome in astrocytoma patients. SYBR Green real-time reverse transcription-polymerase chain reaction assays for quantitation of total and chromosome 2p and 18p specific TERRA levels were developed. Tumor samples from 46 patients with astrocytoma grade 2 to 4, tissue controls, and cell lines were assessed. TMMs were evaluated by measuring TA and by detecting long telomeres due to ALT. In glioblastoma multiforme (GBM) grade 4, total TERRA levels were similar to cell lines but 14-, 31-, and 313-fold lower compared with grade 3, grade 2, and nonmalignant tissue, respectively. Total TERRA levels differed from chromosomal levels. Low 2p TERRA levels correlated with dense promoter methylation of subtelomeric CpG islands, indicating that TERRA expression in gliomas may be chromosome specific and epigenetically regulated. Total TERRA levels correlated with diagnosis, with low or absent TA and the presence of ALT, and were tentatively associated with favorable patient prognosis in our cohort (P = .06). TA and short telomeres identified a subset of GBM with a median survival of only 14.8 months. TERRA and TA may be prognostic in astrocytic tumors.
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    ABSTRACT: Pre-malignant tumor cells enter a state of irreversible cell cycle arrest termed senescence (cellular senescence; CS). CS is a part of the aging program and involves multiple signaling cascades and transduction mechanisms. In general, senescence can be divided into replicative senescence and premature senescence. Replicative senescence (replicative CS) has been described for all metabolically active cells that undergo a spontaneous decline in growth rate. Notably, ectopic expression of telomerase holoenzyme (hTert) can prevent replicative CS. In cancer cells, premature senescence induced by oncogenes, named oncogene-induced senescence (oncogene induced CS; OIS), play an important role in preventing the development of cancer. Oncogene induced CS can be promoted by the loss of tumor suppressor genes, such as PTEN. Additionally, other interesting mechanisms, like selective microRNA expression, epigenetic modifications, or even stress conditions, are also able to activate the senescence program. Here, we will critically review the literature on the role of senescence in preventing the development of cancer and discuss the potential of senescence modulation for generating new molecular tools that could be explored as anticancer treatments.
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