Similar to astragalus, extracts of cycloastragenol can increase telomerase activity. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. An official website of the United States government. and transmitted securely. 2015;65:87108. Therefore, Shang Li developed a short-term expression system for mutant-template telomerase RNA (6). Similarly, using inhibitors of telomerase activity, which prevent telomeric DNA synthesis but do not affect the level of telomerase ribonucleoprotein, elicits the same expected time course of events (Table 1). The activity of telomerase is relatively low in somatic cells and absent in normal cells, . Cancer Ther 2 (2003): 209 -216. Ornish et al (2008) investigated for three months the comprehensive lifestyle changes for 30 men with biopsy-diagnosed low-risk prostate cancer, which led to a significant increase in telomerase activity by 10%. eCollection 2021. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Bethesda, MD 20894, Web Policies The site is secure. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Epub 2022 Oct 10. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. MLL/AF4 suppression diminished telomerase activity and expression of TERT. FOIA J. Mol. Unable to load your collection due to an error, Unable to load your delegates due to an error, Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. Authors have no potential conflicts of interest to disclose. government site. The results are the means SEM (n=3). He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. Ferrara MG, Stefani A, Pilotto S, Carbone C, Vita E, Di Salvatore M, D'Argento E, Sparagna I, Monaca F, Valente G, Vitale A, Piro G, Belluomini L, Milella M, Tortora G, Bria E. Front Oncol. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. DNA methylation of the TERT promoter and its impact on human cancer. Like an aglet, the telomere prevents that end from fraying away. These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . Lancet Oncol. Reproduced from the Proceedings of the National Academy of Sciences, U.S.A., 2001;98:79827 by copyright permission of the National Academy of Sciences, U.S.A. (5). 2006;26(1):91-6. doi: 10.1159/000092031. Mammalian telomeres end in a large duplex loop. HHS Vulnerability Disclosure, Help Unable to load your collection due to an error, Unable to load your delegates due to an error. Bethesda, MD 20894, Web Policies This had the consequence of leaving the telomeric tip uncapped (Fig. Various lines of evidence showed that the cells that grew out were those that either did not receive the lentivector or failed to overexpress the mutant-template telomerase RNA. This inactive complex swamps out the endogenous telomerase. 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. 1996;5:20716. One line of evidence for the lack of p53 protein requirement came from the use of a p53-null human colon cancer cell line kindly provided by Dr. Burt Vogelstein. Proc Am Thorac Soc. In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. As mentioned previously, if telomerase is present in sufficient amounts, it permits cells to keep multiplying. 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. Copyright 2022 by the American Association for Cancer Research. Thus, we converted an effectively immortal, perpetually growing organism into a mortal one by the simple action of making its telomerase nonfunctional, thereby showing that telomerase was important for the continued maintenance of the telomeres and of cell proliferation (3). Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. Telomeres, telomerase, and myc. High telomerase . Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. We could achieve up to about 90% knockdown either by using short hairpin siRNAs expressed in the cells from a lentiviral vector expression cassette or by treating the cancer cells with the short synthetic siRNA oligonucleotides with or without modified backbones (Fig. Interpretation Comprehensive lifestyle changes signi cantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Hence, all one needed to do was spike the endogenous telomerase in the cancer cells with a little mutant-template telomerase RNA that assembled into the telomerase to make mutant repeats. Hence, such a p53-independent apoptotic response is desirable if one is interested in intervening in telomerase action as an anticancer approach. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. 2022 Sep;22(9):515-532. doi: 10.1038/s41568-022-00490-1. . Front Cell Dev Biol. Hence, our attempts to intervene in telomerase action have led us unexpectedly down a new avenue in which we find telomerase doing things that we never expected to see. 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. Telomerase is an enzyme that can rebuild telomeres. The response to mutant-template telomerase RNA is highly specific for cells that have high levels of telomerase. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. Cell. That telomerase knockdown produced down-regulation of a specific subset of genes that included those implicated in tumor progression properties, such as metastasis, was intriguing. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Recent studies also suggest that telomerase is implicated in tumor . Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). The rapid response of telomerase-positive cancer cells to an abrupt depletion of their telomerase despite the lack of telomere uncapping prompted the hypothesis that these effects were unrelated to telomere maintenance or telomere function. Also, Ground flax and chia seeds are excellent vegan sources of short-chain (ALA) omega-3s. In the context of the human body, the fact that the action of telomerase allows cells to keep multiplying can have different kinds of consequences. Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumor cells to die. Cancer Biol Ther. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. The expression of telomerase in various human cancers and its diminished expression in most normal cells suggest that the enzyme might serve as a good target for anticancer drugs. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. Delayed cancer detection is one of the common causes of poor prognosis in case of many cancers including the cancers of the oral cavity. 2. Hence, the DNA at the ends of the chromosomes was effectively naked. Please enable it to take advantage of the complete set of features! Telomeres and human disease: aging, cancer and beyond. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. 2019 Nov 15;105(4):861-874. doi: 10.1016/j.ijrobp.2019.08.009. NOTE: Comparison of human cancer cell growth inhibitory effects predicted and observed when telomerase enzymatic activity was only inhibited (Old) versus those observed in cells in which total telomerase RNA levels were knocked down (New). Hum Genet. Suspi- M.P. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. These proteins include DNA sequencespecific binding proteins and other proteins that together, in effect, sheathe the chromosome end. 2008 Jul;99(7):1385-9. doi: 10.1111/j.1349-7006.2008.00831.x. Geron Corporation GERN, a late-stage clinical biopharmaceutical company, today highlighted multiple additions to its senior commercial leadership team, as it prepares for the potential . Jang JS, Choi YY, Lee WK, Choi JE, Cha SI, Kim YJ, Kim CH, Kam S, Jung TH, Park JY. Herein, an enzyme-free electroanal. Mol Oncol. Federal government websites often end in .gov or .mil. 8600 Rockville Pike eCollection 2021 Jan 19. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. cancer cells employ . The ribozyme treatment decreased the metastatic burden. Disclaimer, National Library of Medicine Keywords: The problem was that previously, the only stable lines that grew out were those that had expressed extremely low levels of mutant-template telomerase RNA. 24 patients had sufficient PBMCs needed for longitudinal analysis. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). 1994;266:20115. Even people living in the Blue Zones eat fish in moderation. "Inhibition of Telomerase activity in human cancer cells by RNA interference". Valdiani A, Ofoghi H, Akbarizare M, Talei D. 3 Biotech. Disclaimer, National Library of Medicine Mutagenesis. Once again, the effects did not require p53 (7). Elizabeth H. Blackburn; Telomerase and Cancer: Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture. Please enable it to take advantage of the complete set of features! We did these experiments in a manner that made the test of the effects as stringent as possible because we did not include a drug selection step after infecting the cells with the lentiviral vectors. 2022 Oct 20;29(10):1517-1531.e7. Their telomeres are mostly maintained at a rather short length; the 40 kb telomeres in LOX melanoma cells are the exception rather than the rule. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. . The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. NCI CPTC Antibody Characterization Program, Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. sharing sensitive information, make sure youre on a federal The https:// ensures that you are connecting to the Accessibility For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. Rapid down-regulation of genes promoting cell cycle progression and metastasis. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. 8600 Rockville Pike Jacobs F, Cani M, Malapelle U, Novello S, Napoli VM, Bironzo P. Cancers (Basel). 3). Telomerase activity can immortalize cancer cells and about 90% of cancers are characterized by increased telomere activity. Epub 2006 Mar 14. Biol 1992;225:95160. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. This increased expression of telomerase makes it an attractive target for intervention. 1999;97:50314. However, development of telomerase inhibitors . Lower left, schematic of the uncapping of telomeres. A complex set of biological functions is encompassed in the word capping of the ends of the chromosomes. Cancer Epidemiol Biomarkers Prev. Such a phospho-profile, termed profile II, cannot fully respond to DNA damage; accumulated p53 remains inactive and does not trigger transcription of its target genes upon stimulus, as compared to the standard phospho-profile I. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. False. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. Epub 2011 Jul 23. 2021 Dec 16;13(24):6332. doi: 10.3390/cancers13246332. -, Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, Nafa K, Riedel ER, Hsu M, Pao W, Miller VA, Ladanyi M. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. and transmitted securely. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Federal government websites often end in .gov or .mil. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Telomere disease. Global cancer statistics, 2012. An official website of the United States government. Telomerase therapy is a promising approach to treating age-related diseases. Through this work, we learned, somewhat to our surprise, that we might also be able to incur a more rapid effect on cancer cell growth than expected and even change their cancerous properties in ways that were hitherto unsuspected (7). It appears that the progressive increase in telomerase activity is associated with the increased level of genomic instability and the phenotypic progression of these premalignant tumors. The "Telomere Erosion in Disposable Soma" theory proposes that replicative loss of telomeric DNA provided a selective advantage during evolution that allowed lifespan to increase by supressing cancer before reproduction (). In contrast to the effects of mutant-template telomerase RNA expression on telomerase RNA knockdown, no telomere shortening or telomere uncapping, or DNA damage response, accompanied the cell growth rate decrease. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. 1999;97:527538. Choi JE, Kang HG, Jang JS, Choi YY, Kim MJ, Kim JS, Jeon HS, Lee WK, Cha SI, Kim CH, Kam S, Jung TH, Park JY. MEK inhibition led to reduced TERT expression and telomerase activity. Indeed, that expected result is exactly what is seen when the telomerase activity in cells is inhibited by, for example, expressing an excess of a catalytically dead version of the protein TERT, which, although it can still assemble into the telomerase ribonucleoprotein complex, forms a complex that is not catalytically active. The https:// ensures that you are connecting to the 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. 2006 Apr;31(3):277-87. doi: 10.1016/j.psyneuen.2005.08.011. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Given this nding and the pilot nature of this study, we report . Epub 2009 Sep 22. PMC Shang Li and Lifeng Xu showed that when we expressed the mutant-template telomerase RNA, even as early as 3 or 4 days after infection, DNA damage foci appeared at the telomeres, as visualized by immunostaining of the telomere-specific protein TRF2. Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy. Weinstein IB. . We were able to show that this also occurs in vivo. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2022 Nov;12(11):319. doi: 10.1007/s13205-022-03373-2. Accessibility The template is only a minor part of the entire telomerase RNA molecule. Disclaimer, National Library of Medicine Careers. Targeting. While the mechanisms for telomerase activation in cancers have not been fully defined, they include telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. Nosrati M, Li S, Bagheri S, et al. Integrin V, which has been implicated in promoting tumor metastasis, was also suppressed. strategy was developed for reliable and highly sensitive telomerase activity assay based on the increased electrochem. It has been postulated that the expression of the ribonucleoprotein telomerase is necessary to overcome cellular senescence and that malignant tumors must express telomerase to maintain their immortality. Interpretation: We expressed the telomerase RNA under a promoter that allowed telomerase to be expressed and active, even in cell lines that normally do not express any telomerase. Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. HHS Vulnerability Disclosure, Help Careers. Increased telomerase activity was associated with a decrease in the level of low-density lipoprotein cholesterol (LDL) and a decrease . Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer. Federal government websites often end in .gov or .mil. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). Previous studies have shown that injecting the telomerase gene into the immune cells (T cells) in our body can help keep the telomeres from getting shorter and enabling them to maintain their anti-viral functioning longer. sharing sensitive information, make sure youre on a federal Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. Although that experiment showed that with enough telomerase the telomeres can be maintained, the length at which they are maintained in a cell is the result of a complex interplay among many different factors. 8600 Rockville Pike sharing sensitive information, make sure youre on a federal The https:// ensures that you are connecting to the Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. The number of papillomas showing higher levels of telomerase activity increased at 20 weeks, and at 30 weeks of promotion, 100% of papillomas expressed significantly higher levels of telomerase. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. Kras mutations upregulate TERT expression, Figure 1. PMC Careers. The Chemopreventive Activity of Indonesia Medicinal Plants Targeting on Hallmarks of Cancer. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. Karadayi S, Arslan S, Sumer Z, Turan M, Sumer H, Karadayi K. Mol Biol Rep. 2013 Aug;40(8):4701-4. doi: 10.1007/s11033-013-2565-8. The telomere, after all, represents a DNA end, which is at the end of the linear chromosomal DNA, but it has to be treated in a different way from an accidental DNA break in a chromosome. Telomere terminal transferase (telomerase) enzyme activity (not the identification of the genes encoding the components of telomerase) was discovered in 1985 in the single-cell organism Tetrahymena ().Almost a decade later, telomerase was described as an almost universal marker in advanced human cancers (), but it was not until 1997 that the catalytic protein component was isolated, first in . Thus, although telomerase is growth-regulated in tissues and cell types that express it, there may be some . This increase coupled with the harsh side effects of some of the cancer chemotherapies have led to the search for more natural biological products, especially those derived from plant . 2022 Sep;16(18):3380-3396. doi: 10.1002/1878-0261.13299. using human cancer cells showed that TERT is a direct target of the Wnt/-catenin pathway and -catenin/TCF4 complex binds to the TERTp and increases telomerase activity An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. Thus, Ashwagandha root extract has the anti-aging inducing potential. Immunity. in patients with breast cancer,4 increased risk of bladder, head and neck, lung, and renal-cell cancers,5 . Hence, the telomeric structure is continually being assembled and disassembled. When compared with the parent cell line, in which the p53 locus is left intact, the responses between the lines were similar. Would you like email updates of new search results? Mutat Res. Larger randomised controlled trials are warranted to confirm the findings of . The .gov means its official. The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. Which of the following statements is accurate about the activity of the telomerase enzyme in cancer cells? Kenessey I, Ki K, Horvth O, Cserepes M, Molnr D, Izsk V, Dobos J, Hegeds B, Tvri J, Tmr J. Oncotarget. Each ribozyme was delivered systemically after B16 cells had been introduced into mice by tail-vein injection. (4) showed in a sufficiency experiment that forced ectopic overexpression of telomerase is sufficient to overcome cellular senescence in culture and maintain the telomeres at a steady length as cells continue to divide. This site needs JavaScript to work properly. But there are risks. 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. Bookshelf Search for other works by this author on: Greider CW, Blackburn EH. 3. This site needs JavaScript to work properly. Approximately 85% of human cancers achieve indefinite cell proliferation and avoidance of telomeric shortening through increased telomerase activity. 2018 Dec 1;24(23):5963-5976. doi: 10.1158/1078-0432.CCR-18-0876. Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, . Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Before Maciejewska N, Olszewski M, Jurasz J, Baginski M, Stasevych M, Zvarych V, Folini M, Zaffaroni N. Cell Death Dis. 2022 Oct 26;14(21):5257. doi: 10.3390/cancers14215257. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. Epub 2008 Apr 29. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. In collaboration with Mohammed Kashani-Sabet and his group at University of California, San Francisco, we examined the effect of telomerase RNA knockdown on metastasis in two in vivo models. Epub 2022 Jul 15. Interestingly, Zhang et al. Similar findings were also made in the setting of a simple xenograft model: When we xenografted human cancer cells expressing the mutant-template telomerase RNA into a mouse model, we saw greatly decreased tumor growth and some regression of the tumors, accompanied by high rates of apoptosis in the tumors (5). Telomerase is a critical factor in CAR-T cell replication and overall function, and its abundance diminishes in cell division, aging, and disease.With reduced telomerase activity, CAR-T cells typically die or become aged, non-functional, and non-proliferating (senescent), leading to inhibited CAR-T function and a lack of prolonged cancer . The fact that telomerase activity declines in somatic cells during adulthood, and that cell transformation and im-mortalization are often associated with increased telom-erase activity (Greider, 1998; Liu, 1999), suggests that telomerase has an antiaging function. The mutated sequence could not bind the DNA sequencespecific protective proteins. Although in many normal adult human cell types telomerase is often expressed at very low, sometimes undetectable, levels, it is clear that telomerase has some protective role in such normal cells. signals of methylene blue (MB) catalyzed by well monodisperse Au nanorods (AuNRs). 2003 Oct 1;289(2):326-34. doi: 10.1016/s0014-4827(03)00281-7. For this reason, some have called telomerase the "immortality enzyme." Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). eCollection 2021 Jun. The site is secure. 4. Gene Dev. HHS Vulnerability Disclosure, Help We were, however, unable to rule out the possibility that telomerase activation over such a short time was a compensatory mechanism induced by adverse conditions (eg, a worsening of prostate cancer). Accessibility Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats. The .gov means its official. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . In the case of humans, the repeat sequence T2AG3 is repeated, in tandem, thousands of times at the end of every chromosome. / Critical Re6iews in Oncology/Hematology 41 (2002) 29-40 37 cious cytogenetic abnormalities in breast cancer corre- with telomerase activity were ultimately diagnosed as late with increased telomerase activity, namely 3q+ carcinoma and 6/7 without telomerase activity were (site of hTR), 8q+ (c-myc), and 17p (p53 .
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increased telomerase activity cancer