OJPathology  Vol.3 No.1 , January 2013
Telomere Maintenance Mechanisms: Prognostic and Therapeutic Implications for the Pathologist and Oncologist
Abstract: In neoplasia, telomere maintenance mechanisms (TMMs) can be prognostic and may direct therapy in the future. Two types of TMM, telomerase and recombination-based alternative lengthening of telomeres (ALT), result in four prognostic tumor groups when they occur individually, in combination, or in mutual absence. Correct designation of the TMM therefore requires an assessment of telomerase activity and for ALT telomere length distribution and ALT associated promyelocytic leukaemia protein (PML) bodies (APBs). The four groups are associated with differing prognoses that are dependent on the tumor type. As TMM inhibitors are developed, oncologists will require that pathologists determine the TMM, and the treatments will differ accordingly. Furthermore, any anti-TMM therapy administered has the potential to selectively change the TMM used by a tumor, necessitating reassessment of the therapeutic strategy. Herein, we review the telomere maintenance mechanisms, the current diagnostic measures and their utility as prognostic markers in the clinical setting.
Cite this paper: N. Hung, H. Hsia, J. Royds and T. Slatter, "Telomere Maintenance Mechanisms: Prognostic and Therapeutic Implications for the Pathologist and Oncologist," Open Journal of Pathology, Vol. 3 No. 1, 2013, pp. 10-20. doi: 10.4236/ojpathology.2013.31003.

[1]   D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell, Vol. 144, No. 5, 2011, pp. 646-674. doi:10.1016/j.cell.2011.02.013

[2]   E. H. Blackburn, C. W. Greider and J. W. Szostak, “Telomeres and Telomerase: The Path from Maize, Tetrahymena and Yeast to Human Cancer and Aging,” Nature Medicine, Vol. 12, No. 10, 2006, pp. 1133-1138. doi:10.1038/nm1006-1133

[3]   S. E. Artandi and R. A. DePinho, “Telomeres and Telomerase in Cancer,” Carcinogenesis, Vol. 31, No. 1, 2010, pp. 9-18. doi:10.1093/carcin/bgp268

[4]   R. K. Moyzis, J. M. Buckingham, L. S. Cram, M. Dani, L. L. Deaven, M. D. Jones, J. Meyne, R. L. Ratliff and J. R. Wu, “A Highly Conserved Repetitive DNA Sequence, (TTAGGG)n, Present at the Telomeres of Human Chromosomes,” Proceedings of the National Academy of Sciences of the United States, Vol. 85, No. 18, 1988, pp. 6622-6626. doi:10.1073/pnas.85.18.6622

[5]   C. B. Harley, A. B. Futcher and C. W. Greider, “Telomeres Shorten during Ageing of Human Fibroblasts,” Nature, Vol. 345, No. 6274, 1990, pp. 458-460. doi:10.1038/345458a0

[6]   A. M. Olovnikov, “A Theory of Marginotomy. The Incomplete Copying of Template Margin in Enzymic Synthesis of Polynucleotides and Biological Significance of the Phenomenon,” Journal of Theoretical Biology, Vol. 41, No. 1, 1973, pp. 181-190. doi:10.1016/0022-5193(73)90198-7

[7]   T. M. Bryan, A. Englezou, J. Gupta, S. Bacchetti and R. R. Reddel, “Telomere Elongation in Immortal Human Cells without Detectable Telomerase Activity,” The EMBO Journal, Vol. 14, No. 17, 1995, pp. 4240-4248.

[8]   T. M. Bryan, A. Englezou, L. Dalla-Pozza, M. A. Dunham and R. R. Reddel, “Evidence for an Alternative Mechanism for Maintaining Telomere Length in Human Tumors and Tumor-Derived Cell Lines,” Nature Medicine, Vol. 3, 11, 1997, pp. 1271-1274. doi:10.1038/nm1197-1271

[9]   J. W. Shay and S. Bacchetti, “A Survey of Telomerase Activity in Human Cancer,” European Journal of Cancer, Vol. 33, No. 5, 1997, pp. 787-791. doi:10.1016/S0959-8049(97)00062-2

[10]   S. T. Durant, “Telomerase-Independent Paths to Immortality in Predictable Cancer Subtypes,” Journal of Cancer, Vol. 3, 2012, pp. 67-82. doi:10.7150/jca.3965

[11]   A. J. Cesare and R. R. Reddel, “Alternative Lengthening of Telomeres: Models, Mechanisms and Implications,” Nature Reviews. Genetics, Vol. 11, No. 5, 2010, pp. 319-330. doi:10.1038/nrg2763

[12]   A. Nabetani and F. Ishikawa, “Alternative Lengthening of Telomeres Pathway: Recombination-Mediated Telomere Maintenance Mechanism in Human Cells,” Journal of Biochemistry, Vol. 149, No. 1, 2011, pp. 5-14. doi:10.1093/jb/mvq119

[13]   J. W. Shay and W. E. Wright, “Role of Telomeres and Telomerase in Cancer,” Seminars in Cancer Biology, Vol. 21, No. 6, 2011, pp. 349-353. doi:10.1016/j.semcancer.2011.10.001

[14]   C. W. Greider and E. H. Blackburn, “Identification of a Specific Telomere Terminal Transferase Activity in Tetrahymena Extracts,” Cell, Vol. 43, No. 2, 1985, pp. 405-413. doi:10.1016/0092-8674(85)90170-9

[15]   C. W. Greider and E. H. Blackburn, “A Telomeric Sequence in the RNA of Tetrahymena Telomerase Required for Telomere Repeat Synthesis,” Nature, Vol. 337, No. 6205, 1989, pp. 331-337. doi:10.1038/337331a0

[16]   S. C. Teng and V. A. Zakian, “Telomere-Telomere Recombination Is an Efficient Bypass Pathway for Telomere Maintenance in Saccharomyces cerevisiae,” Molecular and Cellular Biology, Vol. 19, No. 12, 1999, pp. 8083-8093.

[17]   V. Lundblad and J. W. Szostak, “A Mutant with a Defect in Telomere Elongation Leads to Senescence in Yeast,” Cell, Vol. 57, No. 4, 1989, pp. 633-643. doi:10.1016/0092-8674(89)90132-3

[18]   A. Siddiqa, D. Cavazos, J. Chavez, L. Long and R. A. Marciniak, “Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase,” Journal of Oncology, Vol. 2012, 2012, Article ID: 806382. doi:10.1155/2012/806382

[19]   T. R. Yeager, A. A. Neumann, A. Englezou, L. I. Huschtscha, J. R. Noble and R. R. Reddel, “Telomerase-Negative Immortalized Human Cells Contain a Novel Type of Promyelocytic Leukemia (PML) Body,” Cancer Research, Vol. 59, No. 17, 1999, pp. 4175-4179.

[20]   V. Hakin-Smith, D. A. Jellinek, D. Levy, T. Carroll, M. Teo, W. R. Timperley, M. J. McKay, R. R. Reddel and J. A. Royds, “Alternative Lengthening of Telomeres and Survival in Patients with Glioblastoma Multiforme,” Lancet, Vol. 361, No. 9360, 2003, pp. 836-838. doi:10.1016/S0140-6736(03)12681-5

[21]   K. Hiyama, E. Hiyama, S. Ishioka, M. Yamakido, K. Inai, A. F. Gazdar, M. A. Piatyszek and J. W. Shay, “Telomerase Activity in Small-Cell and Non-Small-Cell Lung Cancers,” Journal of the National Cancer Institute, Vol. 87, No. 12, 1995, pp. 895-902. doi:10.1093/jnci/87.12.895

[22]   E. Hiyama, L. Gollahon, T. Kataoka, K. Kuroi, T. Yokoyama, A. F. Gazdar, K. Hiyama, M. A. Piatyszek and J. W. Shay, “Telomerase Activity in Human Breast Tumors,” Journal of the National Cancer Institute, Vol. 88, No. 2, pp. 1996, pp. 116-122. doi:10.1093/jnci/88.2.116

[23]   N. Tatsumoto, E. Hiyama, Y. Murakami, Y. Imamura, J. W. Shay, Y. Matsuura and T. Yokoyama, “High Telomerase Activity Is an Independent Prognostic Indicator of Poor Outcome in Colorectal Cancer,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, Vol. 6, No. 7, 2000, pp. 2696-2701.

[24]   C. M. Buseman, W. E. Wright, J. W. Shay, “Is Telomerase a Viable Target in Cancer?” Mutation Research, Vol. 730, No. 1-2, 2012, pp. 90-97 doi:10.1016/j.mrfmmm.2011.07.006.

[25]   J. Hu, S. S. Hwang, M. Liesa, B. Gan, E. Sahin, M. Jaskelioff, Z. Ding, H. Ying, A. T. Boutin, H. Zhang, S. Johnson, E. Ivanova, M. Kost-Alimova, A. Protopopov, Y. A. Wang, O. S. Shirihai, L. Chin and R. A. DePinho, “Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer,” Cell, Vol. 148, No. 4, 2012, pp. 651-663. doi:10.1016/j.cell.2011.12.028

[26]   A. K. Meeker and D. S. Coffey, “Telomerase: A Promising Marker of Biological Immortality of Germ, Stem, and Cancer Cells. A Review,” Biochemistry (Moscow), Vol. 62, No. 11, 1997, pp. 1323-1331.

[27]   J. E. Johnson and D. Broccoli, “Telomere Maintenance in Sarcomas,” Current Opinion in Oncology, Vol. 19, No. 4, 2007, pp. 377-382. doi:10.1097/CCO.0b013e3281214423

[28]   J. D. Henson and R. R. Reddel, “Assaying and Investigating Alternative Lengthening of Telomeres Activity in Human Cells and Cancers,” FEBS Letters, Vol. 584, No. 17, 2010, pp. 3800-3811. doi:10.1016/j.febslet.2010.06.009

[29]   C. M. Heaphy, A. P. Subhawong, S. M. Hong, M. G. Goggins, E. A. Montgomery, E. Gabrielson, G. J. Netto, J. I. Epstein, T. L. Lotan, W. H. Westra, M. Shih Ie, C. A. Iacobuzio-Donahue, A. Maitra, Q. K. Li, C. G. Eberhart, J. M. Taube, D. Rakheja, R. J. Kurman, T. C. Wu, R. B. Roden, P. Argani, A. M. De Marzo, L. Terracciano, M. Torbenson and A. K. Meeker, “Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes,” American Journal of Pathology, Vol. 179, No. 4, 2011, pp. 1608-1615. doi:10.1016/j.ajpath.2011.06.018

[30]   A. P. Subhawong, C. M. Heaphy, P. Argani, Y. Konishi, N. Kouprina, H. Nassar, R. Vang and A. K. Meeker, “The Alternative Lengthening of Telomeres Phenotype in Breast Carcinoma Is Associated with HER-2 Overexpression,” Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc., Vol. 22, No. 11, 2009, pp. 1423-1431.

[31]   Y. K. Lee, N. H. Park and H. Lee, “Prognostic Value of Alternative Lengthening of Telomeres-Associated Biomarkers in Uterine Sarcoma and Uterine Carcinosarcoma,” International Journal of Gynecological Cancer, Vol. 22, No. 3, 2012, pp. 434-441. doi:10.1097/IGC.0b013e31823ca017

[32]   G. A. Ulaner, A. R. Hoffman, J. Otero, H. Y. Huang, Z. Zhao, M. Mazumdar, R. Gorlick, P. Meyers, J. H. Healey and M. Ladanyi, “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, Vol. 41, No. 2, 2004, pp. 155-162. doi:10.1002/gcc.20074

[33]   E. Montgomery, P. Argani, J. L. Hicks, A. M. DeMarzo and A. K. Meeker, “Telomere Lengths of Translocation-Associated and Nontranslocation-Associated Sarcomas Differ Dramatically,” American Journal of Pathology, Vol. 164, No. 5, 2004, pp. 1523-1529. doi:10.1016/S0002-9440(10)63710-8

[34]   U. Tabori, B. Vukovic, M. Zielenska, C. Hawkins, I. Braude, J. Rutka, E. Bouffet, J. Squire and D. Malkin, “The Role of Telomere Maintenance in the Spontaneous Growth Arrest of Pediatric Low-Grade Gliomas,” Neoplasia, Vol. 8, No. 2, 2006, pp. 136-142. doi:10.1593/neo.05715

[35]   T. Slatter, J. Gifford-Garner, A. Wiles, X. Tan, Y. J. Chen, M. MacFarlane, M. Sullivan, J. Royds and N. Hung, “Pilocytic Astrocytomas Have Telomere-Associated Promyelocytic Leukemia Bodies without Alternatively Lengthened Telomeres,” American Journal of Pathology, Vol. 177, No. 6, 2010, pp. 2694-2700. doi:10.2353/ajpath.2010.100468

[36]   J. D. Henson, J. A. Hannay, S. W. McCarthy, J. A. Royds, T. R. Yeager, R. A. Robinson, S. B. Wharton, D. A. Jellinek, S. M. Arbuckle, J. Yoo, B. G. Robinson, D. L. Learoyd, P. D. Stalley, S. F. Bonar, D. Yu, R. E. Pollock and R. R. Reddel, “A Robust Assay for Alternative Lengthening of Telomeres in Tumors Shows the Significance of Alternative Lengthening of Telomeres in Sarcomas and Astrocytomas,” Clinical Cancer Research, Vol. 11, No. 1, 2005, pp. 217-225.

[37]   J. A. Royds, S. Al Nadaf, A. K. Wiles, Y. J. Chen, A. Ahn, A. Shaw, S. Bowie, F. Lam, B. C. Baguley, A. W. Braithwaite, M. R. MacFarlane, N. A. Hung and T. L. Slatter, “The CDKN2A G500 Allele Is More Frequent in GBM Patients with No Defined Telomere Maintenance Mechanism Tumors and Is Associated with Poorer Survival,” PLoS One, Vol. 6, No. 10, 2011, p. e26737. doi:10.1371/journal.pone.0026737

[38]   L. Venturini, M. G. Daidone, R. Motta, P. Collini, F. Spreafico, M. Terenziani, L. Piva, P. Radice, D. Perotti and N. Zaffaroni, “Telomere Maintenance in Wilms Tumors: First Evidence for the Presence of Alternative Lengthening of Telomeres Mechanism,” Genes, Chromosomes & Cancer, Vol. 50, No. 10, 2011, pp. 823-829. doi:10.1002/gcc.20903

[39]   A. Costa, M. G. Daidone, L. Daprai, R. Villa, S. Cantu, S. Pilotti, L. Mariani, A. Gronchi, J. D. Henson, R. R. Reddel and N. Zaffaroni, “Telomere Maintenance Mechanisms in Liposarcomas: Association with Histologic Subtypes and Disease Progression,” Cancer Research, Vol. 66, No. 17, 2006, pp. 8918-8924. doi:10.1158/0008-5472.CAN-06-0273

[40]   L. Venturini, R. Motta, A. Gronchi, M. Daidone and N. Zaffaroni, “Prognostic Relevance of ALT-Associated Markers in Liposarcoma: A Comparative Analysis,” BMC Cancer, Vol. 10, 2010, p. 254. doi:10.1186/1471-2407-10-254

[41]   G. A. Ulaner, H. Y. Huang, J. Otero, Z. Zhao, L. Ben-Porat, J. M. Satagopan, R. Gorlick, P. Meyers, J. H. Healey, A. G. Huvos, A. R. Hoffman and M. Ladanyi, “Absence of a Telomere Maintenance Mechanism as a Favorable Prognostic Factor in Patients with Osteosarcoma,” Cancer Research, Vol. 63, No. 8, 2003, pp. 1759-1763.

[42]   A. Ohali, S. Avigad, S. Ash, Y. Goshen, D. Luria, M. Feinmesser, R. Zaizov and I. Yaniv, “Telomere Length Is A Prognostic Factor in Neuroblastoma,” Cancer, Vol. 107, No. 6, 2006, pp. 1391-1399. doi:10.1002/cncr.22132

[43]   L. Venturini, M. G. Daidone, R. Motta, G. Cimino-Reale, S. F. Hoare, A. Gronchi, M. Folini, W. N. Keith and N. Zaffaroni, “Telomere Maintenance Mechanisms in Malignant Peripheral Nerve Sheath Tumors: Expression and Prognostic Relevance,” Neuro-Oncology, Vol. 14, No. 6, 2012, pp. 736-744. doi:10.1093/neuonc/nos083

[44]   R. Villa, M. G. Daidone, R. Motta, L. Venturini, C. De Marco, A. Vannelli, S. Kusamura, D. Baratti, M. Deraco, A. Costa, R. R. Reddel and N. Zaffaroni, “Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma,” Clinical Cancer Research, Vol. 14, No. 13, 2008, pp. 4134-4140. doi:10.1158/1078-0432.CCR-08-0099

[45]   I. Chung, S. Osterwald, K. I. Deeg and K. Rippe, “PML Body Meets Telomere: The Beginning of an ALTernate Ending?” Nucleus, Vol. 3, No. 3, 2012, pp. 263-275. doi:10.4161/nucl.20326

[46]   J. Fajkus, “Detection of Telomerase Activity by the TRAP Assay and Its Variants and Alternatives,” Clinica chimica Acta; International Journal of Clinical Chemistry, Vol. 371, v1-2, 2006, pp. 25-31.

[47]   N. W. Kim, M. A. Piatyszek, K. R. Prowse, C. B. Harley, M. D. West, P. L. Ho, G. M. Coviello, W. E. Wright, S. L. Weinrich and J. W. Shay, “Specific Association of Human Telomerase Activity with Immortal Cells and Cancer,” Science, Vol. 266, No. 5193, 1994, pp. 2011-2015. doi:10.1126/science.7605428

[48]   L. R. Gauthier, C. Granotier, J. C. Soria, S. Faivre, V. Boige, E. Raymond and F. D. Boussin, “Detection of Circulating Carcinoma Cells by Telomerase Activity,” British Journal of Cancer, Vol. 84, No. 5, 2001, pp. 631-635. doi:10.1054/bjoc.2000.1662

[49]   K. Ohyashiki, J. H. Ohyashiki, J. Nishimaki, K. Toyama, Y. Ebihara, H. Kato, W. E. Wright and J. W. Shay, “Cytological Detection of Telomerase Activity Using an in Situ Telomeric Repeat Amplification Protocol Assay,” Cancer Research, Vol. 57, No. 11, 1997, pp. 2100-2103.

[50]   C. Maesawa, T. Inaba, H. Sato, S. Iijima, K. Ishida, M. Terashima, R. Sato, M. Suzuki, A. Yashima, S. Ogasawara, H. Oikawa, N. Sato, K. Saito and T. Masuda, “A Rapid Biosensor Chip Assay for Measuring of Telomerase Activity Using Surface Plasmon Resonance,” Nucleic Acids Research, Vol. 31, No. 2, 2003, p. E4. doi:10.1093/nar/gng004

[51]   E. Hiyama, K. Hiyama, T. Yokoyama and J. W. Shay, “Immunohistochemical Detection of Telomerase (hTERT) Protein in Human Cancer Tissues and a Subset of Cells in Normal Tissues,” Neoplasia, Vol. 3, No. 1, 2001, pp. 17-26. doi:10.1038/sj.neo.7900134

[52]   P. Yan, J. Benhattar, W. Seelentag, J. C. Stehle and F. T. Bosman, “Immunohistochemical Localization of hTERT Protein in Human Tissues,” Histochemistry and Cell Biology, Vol. 121, No. 5, 2004, pp. 391-397. doi:10.1007/s00418-004-0645-5

[53]   C. Dudognon, F. Pendino, J. Hillion, A. Saumet, M. Lanotte and E. Segal-Bendirdjian, “Death Receptor Signaling Regulatory Function for Telomerase: hTERT Abolishes TRAIL-Induced Apoptosis, Independently of Telomere Maintenance,” Oncogene, Vol. 23, No. 45, 2004, pp. 7469-7474. doi:10.1038/sj.onc.1208029

[54]   W. Fu, J. G. Begley, M. W. Killen and M. P. Mattson, “Anti-Apoptotic Role of Telomerase in Pheochromocytoma Cells,” the Journal of Biological Chemistry, Vol. 274, No. 11, 1999, pp. 7264-7271. doi:10.1074/jbc.274.11.7264

[55]   A. Kilian, D. D. Bowtell, H. E. Abud, G. R. Hime, D. J. Venter, P. K. Keese, E. L. Duncan, R. R. Reddel and R. A. Jefferson, “Isolation of a Candidate Human Telomerase Catalytic Subunit Gene, Which Reveals Complex Splicing Patterns in Different Cell Types,” Human Molecular Genetics, Vol. 6, No. 12, 1997, pp. 2011-2019. doi:10.1093/hmg/6.12.2011

[56]   J. S. Shin, T. Foo, A. Hong, M. Zhang, T. Lum, M. J. Solomon and C. S. Lee, “Telomerase Expression as a Predictive Marker of Radiotherapy Response in Rectal Cancer,” Pathology, Vol. 44, No. 3, 2012, pp. 209-215. doi:10.1097/PAT.0b013e3283511cd5

[57]   S. Sampl, S. Pramhas, C. Stern, M. Preusser, C. Marosi and K. Holzmann, “Expression of Telomeres in Astrocytoma WHO Grade 2 to 4: TERRA Level Correlates with Telomere Length, Telomerase Activity and Advanced Clinical Grade,” Translational Oncology, Vol. 5, No. 1, 2012, pp. 56-65.

[58]   C. M. Azzalin, P. Reichenbach, L. Khoriauli, E. Giulotto and J. Lingner, “Telomeric Repeat Containing RNA and RNA Surveillance Factors at Mammalian Chromosome Ends,” Science, Vol. 318, No. 5851, 2007, pp. 798-801. doi:10.1126/science.1147182

[59]   S. Schoeftner and M. A. Blasco, “Developmentally Regulated Transcription of Mammalian Telomeres by DNA-Dependent RNA Polymerase II,” Nature Cell Biology, Vol. 10, No. 2, 2008, pp. 228-236. doi:10.1038/ncb1685

[60]   J. P. Issa, “CpG Island Methylator Phenotype in Cancer,” Nature Reviews Cancer, Vol. 4, No. 12, 2004, pp. 988-993. doi:10.1038/nrc1507

[61]   M. Esteller, “Cancer Epigenomics: DNA Methylomes and Histone-Modification Maps,” Nature Reviews Genetics, Vol. 8, No. 4, 2007, pp. 286-298. doi:10.1038/nrg2005

[62]   J. P. Issa, N. Ahuja, M. Toyota, M. P. Bronner and T. A. Brentnall, “Accelerated Age-Related CpG Island Methylation in Ulcerative Colitis,” Cancer Research, Vol. 61, No. 9, 2001, pp. 3573-3577.

[63]   B. Luke, A. Panza, S. Redon, N. Iglesias, Z. Li and J. Lingner, “The Rat1p 5’to 3’ Exonuclease Degrades Telomeric Repeat-Containing RNA and Promotes Telomere Elongation in Saccharomyces cerevisiae,” Molecular Cell, Vol. 32, No. 4, 2008, pp. 465-477. doi:10.1016/j.molcel.2008.10.019

[64]   R. M. Cawthon, “Telomere Measurement by Quantitative PCR,” Nucleic Acids Research, Vol. 30, No. 10, 2002, p. e47. doi:10.1093/nar/30.10.e47

[65]   N. O’Callaghan, V. Dhillon, P. Thomas and M. Fenech, “A Quantitative Real-Time PCR Method for Absolute Telomere Length,” BioTechniques, Vol. 44, 6, 2008, pp. 807-809. doi:10.2144/000112761

[66]   J. D. Henson and R. R. Reddel, “Assaying and Investigating Alternative Lengthening of Telomeres Activity in Human Cells and Cancers,” FEBS Letters, Vol. 584, No. 17, 2010, pp. 3800-3811. doi:10.1016/j.febslet.2010.06.009

[67]   T. L. Slatter, X. Tan, Y. C. Yuen, S. Gunningham, S. S. Ma, E. Daly, S. Packer, C. Devenish, J. A. Royds and N. A. Hung, “The Alternative Lengthening of Telomeres Pathway May Operate in Non-Neoplastic Human Cells,” The Journal of Pathology, Vol. 226, No. 3, 2012, pp. 509-518. doi:10.1002/path.2981

[68]   C. L. Fasching, A. A. Neumann, A. Muntoni, T. R. Yeager and R. R. Reddel, “DNA Damage Induces Alternative Lengthening of Telomeres (ALT) associated Promyelocytic Leukemia Bodies That Preferentially Associate with Linear Telomeric DNA,” Cancer Research, Vol. 67, No. 15, 2007, pp. 7072-7077. doi:10.1158/0008-5472.CAN-07-1556

[69]   C. L. Fasching, K. Bower and R. R. Reddel, “Telomerase-Independent Telomere Length Maintenance in the Absence of Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Bodies,” Cancer Research, Vol. 65, No. 7, 2005, pp. 2722-2729. doi:10.1158/0008-5472.CAN-04-2881

[70]   J. N. Jeyapalan, A. Mendez-Bermudez, N. Zaffaroni, Y. E. Dubrova and N. J. Royle, “Evidence for alternative Lengthening of Telomeres in Liposarcomas in the Absence of ALT-Associated PML Bodies,” International Journal of Cancer, Vol. 122, No. 11, 2008, pp. 2414-2421. doi:10.1002/ijc.23412

[71]   J. D. Henson, Y. Cao, L. I. Huschtscha, A. C. Chang, A. Y. Au, H. A. Pickett and R. R. Reddel, “DNA C-Circles Are Specific and Quantifiable Markers of Alternative-Lengthening-of-Telomeres Activity,” Nature Biotechnology, Vol. 27, No. 12, 2009, pp. 1181-1185. doi:10.1038/nbt.1587

[72]   S. Gonzalo, I. Jaco, M. F. Fraga, T. Chen, E. Li, M. Esteller and M. A. Blasco, “DNA Methyltransferases Control Telomere Length and Telomere Recombination in Mammalian Cells,” Nature Cell Biology, Vol. 8, No. 4, 2006, pp. 416-424. doi:10.1038/ncb1386

[73]   R. G. Verhaak, K. A. Hoadley, E. Purdom, V. Wang, Y. Qi, M. D. Wilkerson, C. R. Miller, L. Ding, T. Golub, J. P. Mesirov, G. Alexe, M. Lawrence, M. O’Kelly, P. Tamayo, B. A. Weir, S. Gabriel, W. Winckler, S. Gupta, L. Jakkula, H. S. Feiler, J. G. Hodgson, C. D. James, J. N. Sarkaria, C. Brennan, A. Kahn, P. T. Spellman, R. K. Wilson, T. P. Speed, J. W. Gray, M. Meyerson, G. Getz, C. M. Perou and D. N. Hayes, “Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR and NF1,” Cancer Cell, Vol. 17, No. 1, 2010, pp. 98-110. doi:10.1016/j.ccr.2009.12.020

[74]   D. W. Parsons, S. Jones, X. Zhang, J. C. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, I. M. Siu, G. L. Gallia, A. Olivi, R. McLendon, B. A. Rasheed, S. Keir, T. Nikolskaya, Y. Nikolsky, D. A. Busam, H. Tekleab, L. A. Diaz, Jr., J. Hartigan, D. R. Smith, R. L. Strausberg, S. K. Marie, S. M. Shinjo, H. Yan, G. J. Riggins, D. D. Bigner, R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V. E. Velculescu and K. W. Kinzler, “An Integrated Genomic Analysis of Human Glioblastoma Multiforme,” Science, Vol. 321, No. 5897, 2008, pp. 1807-1812. doi:10.1126/science.1164382

[75]   H. Yan, D. W. Parsons, G. Jin, R. McLendon, B. A. Rasheed, W. Yuan, I. Kos, I. Batinic-Haberle, S. Jones, G. J. Riggins, H. Friedman, A. Friedman, D. Reardon, J. Herndon, K. W. Kinzler, V. E. Velculescu, B. Vogelstein and D. D. Bigner, “IDH1 and IDH2 Mutations in Gliomas,” The New England Journal of Medicine, Vol. 360, 2009, pp. 765-773. doi:10.1056/NEJMoa0808710

[76]   J. Balss, J. Meyer, W. Mueller, A. Korshunov, C. Hartmann and A. von Deimling, “Analysis of the IDH1 Codon 132 Mutation in Brain Tumors,” Acta Neuropathologica, Vol. 116, No. 6, 2008, pp. 597-602. doi:10.1007/s00401-008-0455-2

[77]   K. L. McDonald, J. McDonnell, A. Muntoni, J. D. Henson, M. E. Hegi, A. von Deimling, H. R. Wheeler, R. J. Cook, M. T. Biggs, N. S. Little, B. G. Robinson, R. R. Reddel and J. A. Royds, “Presence of Alternative Lengthening of Telomeres Mechanism in Patients with Glioblastoma Identifies a Less Aggressive Tumor Type with Longer Survival,” Journal of Neuropathology & Experimental Neurology, Vol. 69, No. 7, 2010, pp. 729-736. doi:10.1097/NEN.0b013e3181e576cf

[78]   D. Capper, H. Zentgraf, J. Balss, C. Hartmann and A. von Deimling, “Monoclonal Antibody Specific for IDH1 R132H Mutation,” Acta neuropathologica, Vol. 118, No. 5, 2009, pp. 599-601. doi:10.1007/s00401-009-0595-z

[79]   C. M. Heaphy, R. F. de Wilde, Y. Jiao, A. P. Klein, B. H. Edil, C. Shi, C. Bettegowda, F. J. Rodriguez, C. G. Eberhart, S. Hebbar, G. J. Offerhaus, R. McLendon, B. A. Rasheed, Y. He, H. Yan, D. D. Bigner, S. M. Oba-Shinjo, S. K. Marie, G. J. Riggins, K. W. Kinzler, B. Vogelstein, R. H. Hruban, A. Maitra, N. Papadopoulos and A. K. Meeker, “Altered Telomeres in Tumors with ATRX and DAXX Mutations,” Science, Vol. 333, No. 6041, 2011, p. 425. doi:10.1126/science.1207313

[80]   J. Schwartzentruber, A. Korshunov, X. Y. Liu, D. T. Jones, E. Pfaff, K. Jacob, D. Sturm, A. M. Fontebasso, D. A. Quang, M. Tonjes, V. Hovestadt, S. Albrecht, M. Kool, A. Nantel, C. Konermann, A. Lindroth, N. Jager, T. Rausch, M. Ryzhova, J. O. Korbel, T. Hielscher, P. Hauser, M. Garami, A. Klekner, L. Bognar, M. Ebinger, M. U. Schuhmann, W. Scheurlen, A. Pekrun, M. C. Fruhwald, W. Roggendorf, C. Kramm, M. Durken, J. Atkinson, P. Lepage, A. Montpetit, M. Zakrzewska, K. Zakrzewski, P. P. Liberski, Z. Dong, P. Siegel, A. E. Kulozik, M. Zapatka, A. Guha, D. Malkin, J. Felsberg, G. Reifenberger, A. von Deimling, K. Ichimura, V. P. Collins, H. Witt, T. Milde, O. Witt, C. Zhang, P. Castelo-Branco, P. Lichter, D. Faury, U. Tabori, C. Plass, J. Majewski, S. M. Pfister and N. Jabado, “Driver Mutations in Histone H3.3 and Chromatin Remodelling Genes in Paediatric Glioblastoma,” Nature, Vol. 482, No. 7384, 2012, pp. 226-231. doi:10.1038/nature10833

[81]   G. Wu, A. Broniscer, T. A. McEachron, C. Lu, B. S. Paugh, J. Becksfort, C. Qu, L. Ding, R. Huether, M. Parker, J. Zhang, A. Gajjar, M. A. Dyer, C. G. Mullighan, R. J. Gilbertson, E. R. Mardis, R. K. Wilson, J. R. Downing, D. W. Ellison and S. J. Baker, “Somatic Histone H3 Alterations in Pediatric Diffuse Intrinsic Pontine Gliomas and Non-Brainstem Glioblastomas,” Nature Genetics, Vol. 44, No. 3, 2012, pp. 251-253. doi:10.1038/ng.1102

[82]   C. J. Cairney, S. F. Hoare, M. G. Daidone, N. Zaffaroni and W. N. Keith, “High Level of Telomerase RNA Gene Expression Is Associated with Chromatin Modification, the ALT Phenotype and Poor Prognosis in Liposarcoma,” British Journal of Cancer, Vol. 98, No. 8, 2008, pp. 1467-1474. doi:10.1038/sj.bjc.6604328

[83]   Y. J. Chen, V. Hakin-Smith, M. Teo, G. E. Xinarianos, D. A. Jellinek, T. Carroll, D. McDowell, M. R. MacFarlane, R. Boet, B. C. Baguley, A. W. Braithwaite, R. R. Reddel and J. A. Royds, “Association of Mutant TP53 with Alternative Lengthening of Telomeres and Favorable Prognosis in Glioma,” Cancer Research, Vol. 66, No. 13, 2006, pp. 6473-6476. doi:10.1158/0008-5472.CAN-06-0910

[84]   C. Lu, P. S. Ward, G. S. Kapoor, D. Rohle, S. Turcan, O. Abdel-Wahab, C. R. Edwards, R. Khanin, M. E. Figueroa, A. Melnick, K. E. Wellen, D. M. O’Rourke, S. L. Berger, T. A. Chan, R. L. Levine, I. K. Mellinghoff and C. B. Thompson, “IDH Mutation Impairs Histone Demethylation and Results in a Block to Cell Differentiation,” Nature, Vol. 483, No. 7390, 2012, pp. 474-478. doi:10.1038/nature10860

[85]   D. C. Silvestre, J. R. Pineda, F. Hoffschir, J. M. Studler, M. A. Mouthon, F. Pflumio, M. P. Junier, H. Chneiweiss and F. D. Boussin, “Alternative Lengthening of Telomeres in Human Glioma Stem Cells,” Stem Cells, Vol. 29, No. 3, 2011, pp. 440-451. doi:10.1002/stem.600

[86]   M. F. Amary, K. Bacsi, F. Maggiani, S. Damato, D. Halai, F. Berisha, R. Pollock, P. O’Donnell, A. Grigoriadis, T. Diss, M. Eskandarpour, N. Presneau, P. C. Hogendoorn, A. Futreal, R. Tirabosco and A. M. Flanagan, “IDH1 and IDH2 Mutations Are Frequent Events in Central Chondrosarcoma and Central and Periosteal Chondromas But Not in Other Mesenchymal Tumors,” The Journal of Pathology, Vol. 224, No. 3, 2011, pp. 334-343. doi:10.1002/path.2913

[87]   R. L. Giuntoli, 2nd, D. S. Metzinger, C. S. DiMarco, S. S. Cha, J. A. Sloan, G. L. Keeney and B. S. Gostout, “Retrospective Review of 208 Patients with Leiomyosarcoma of the Uterus: Prognostic Indicators, Surgical Management, and Adjuvant Therapy,” Gynecologic Oncology, Vol. 89, No. 3, 2003, pp. 460-469. doi:10.1016/S0090-8258(03)00137-9

[88]   R. Tomoda, M. Seto, H. Tsumuki, K. Iida, T. Yamazaki, J. Sonoda, A. Matsumine and A. Uchida, “Telomerase Activity and Human Telomerase Reverse Transcriptase mRNA Expression Are Correlated with Clinical Aggressiveness in Soft Tissue Tumors,” Cancer, Vol. 95, No. 5, 2002, pp. 1127-1133. doi:10.1002/cncr.10793

[89]   K. Aogi, A. Woodman, V. Urquidi, D. C. Mangham, D. Tarin and S. Goodison, “Telomerase Activity in Soft-Tissue and Bone Sarcomas,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, Vol. 6, No. 12, 2000, pp. 4776-4781.