Clinical Relevance of Alternative Lengthening of Telomeres in Cancer

Guilherme    G.   da Silva; Karollyne    S.   Morais; Daniel    S.   Arcanjo; Diêgo    M.   de Oliveira
Abstract

The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Moreover, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of the telomere. However, ALT has been implicated in different – sometimes opposite – outcomes, according to the tumor type studied. Then, in order to design and develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.
Keywords: ALT, Cancer, Telomeres, Telomerase, Cell immortalization, Oncology.
Graphical Abstract

[1] 
Bernardes de Jesus, B.; Blasco, M.A. Telomerase at the intersection of cancer and aging. Trends Genet.,  2013, 29(9), 513-520.
[http://dx.doi.org/10.1016/j.tig.2013.06.007] [PMID: 23876621] 
[2] 
Kong, F.; Zheng, C.; Xu, D. Telomerase as a “stemness” enzyme. Sci. China Life Sci.,  2014, 57(6), 564-570.
[http://dx.doi.org/10.1007/s11427-014-4666-6] [PMID: 24829107] 
[3] 
Avilion, A.A.; Piatyszek, M.A.; Gupta, J.; Shay, J.W.; Bacchetti, S.; Greider, C.W. Human telomerase RNA and telomerase activity in immortal cell lines and tumor tissues. Cancer Res.,  1996, 56(3), 645-650.
[PMID: 8564985] 
[4] 
Feijoo, P.; Dominguez, D.; Tusell, L.; Genesca, A. Telomere-dependent genomic integrity: evolution of the fusion-bridge-breakage cycle concept. Curr. Pharm. Des.,  2014, 20(41), 6375-6385.
[http://dx.doi.org/10.2174/1381612820666140630085416] [PMID: 24975612] 
[5] 
Bär, C.; Blasco, M.A. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000 Res.,  2016, 5, F1000.
[http://dx.doi.org/10.12688/f1000research.7020.1] [PMID: 27081482] 
[6] 
Jafri, M.A.; Ansari, S.A.; Alqahtani, M.H.; Shay, J.W. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med.,  2016, 8(1), 69.
[http://dx.doi.org/10.1186/s13073-016-0324-x] [PMID: 27323951] 
[7] 
Bryan, T.M.; Englezou, A.; Gupta, J.; Bacchetti, S.; Reddel, R.R. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J.,  1995, 14(17), 4240-4248.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00098.x] [PMID: 7556065] 
[8] 
Bryan, T.M.; Englezou, A.; Dalla-Pozza, L.; Dunham, M.A.; Reddel, R.R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat. Med.,  1997, 3(11), 1271-1274.
[http://dx.doi.org/10.1038/nm1197-1271] [PMID: 9359704] 
[9] 
Cesare, A.J.; Reddel, R.R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genet.,  2010, 11(5), 319-330.
[http://dx.doi.org/10.1038/nrg2763] [PMID: 20351727] 
[10] 
Wojtyla, A.; Gladych, M.; Rubis, B. Human telomerase activity regulation. Mol. Biol. Rep.,  2011, 38(5), 3339-3349.
[http://dx.doi.org/10.1007/s11033-010-0439-x] [PMID: 21086176] 
[11] 
Draskovic, I.; Londono-Vallejo, A. Telomere recombination and the ALT pathway: a therapeutic perspective for cancer. Curr. Pharm. Des.,  2014, 20(41), 6466-6471.
[http://dx.doi.org/10.2174/1381612820666140630085857] [PMID: 24975611] 
[12] 
Pompili, L.; Leonetti, C.; Biroccio, A.; Salvati, E. Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option? J. Exp. Clin. Cancer Res.,  2017, 36(1), 189.
[http://dx.doi.org/10.1186/s13046-017-0657-3] [PMID: 29273061] 
[13] 
Murnane, J.P.; Sabatier, L.; Marder, B.A.; Morgan, W.F. Telomere dynamics in an immortal human cell line. EMBO J.,  1994, 13(20), 4953-4962.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06822.x] [PMID: 7957062] 
[14] 
Henderson, S.; Allsopp, R.; Spector, D.; Wang, S.S.; Harley, C. In situ analysis of changes in telomere size during replicative aging and cell transformation. J. Cell Biol.,  1996, 134(1), 1-12.
[http://dx.doi.org/10.1083/jcb.134.1.1] [PMID: 8698806] 
[15] 
Barroso-González, J.; García-Expósito, L.; Hoang, S.M.; Lynskey, M.L.; Roncaioli, J.L.; Ghosh, A.; Wallace, C.T.; Modesti, M.; Bernstein, K.A.; Sarkar, S.N.; Watkins, S.C.; O’Sullivan, R.J. RAD51AP1 is an essential mediator of alternative lengthening of telomeres. Mol. Cell,  2019, 76, 1-16.
[http://dx.doi.org/10.1016/j.molcel.2019.08.009] 
[16] 
Ge, Y.; Wu, S.; Zhang, Z.; Li, X.; Li, F.; Yan, S.; Liu, H.; Huang, J.; Zhao, Y. Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers. Protein Cell,  2019, 1-17.
[http://dx.doi.org/10.1007/s13238-019-0634-z] 
[17] 
Gaspar, T.B.; Sá, A.; Lopes, J.M.; Sobrinho-Simões, M.; Soares, P.; Vinagre, J. Telomere maintenance mechanisms in cancer. Genes (Basel),  2018, 9(5), E241
[http://dx.doi.org/10.3390/genes9050241] [PMID: 29751586] 
[18] 
Folini, M.; Venturini, L.; Cimino-Reale, G.; Zaffaroni, N. Telomeres as targets for anticancer therapies. Expert Opin. Ther. Targets,  2011, 15(5), 579-593.
[http://dx.doi.org/10.1517/14728222.2011.556621] [PMID: 21288186] 
[19] 
Karnitz, L.M.; Zou, L. Molecular pathways: Targeting ATR in cancer therapy. Clin. Cancer Res.,  2015, 21(21), 4780-4785.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0479] [PMID: 26362996] 
[20] 
Santambrogio, F.; Gandellini, P.; Cimino-Reale, G.; Zaffaroni, N.; Folini, M. MicroRNA-dependent regulation of telomere maintenance mechanisms: a field as much unexplored as potentially promising. Curr. Pharm. Des.,  2014, 20(41), 6404-6421.
[http://dx.doi.org/10.2174/1381612820666140630095918] [PMID: 24975607] 
[21] 
Pan, X.; Drosopoulos, W.C.; Sethi, L.; Madireddy, A.; Schildkraut, C.L.; Zhang, D. FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres. Proc. Natl. Acad. Sci. USA,  2017, 114(29), E5940-E5949.
[http://dx.doi.org/10.1073/pnas.1708065114] [PMID: 28673972] 
[22] 
Lu, R.; O’Rourke, J.J.; Sobinoff, A.P.; Allen, J.A.M.; Nelson, C.B.; Tomlinson, C.G.; Lee, M.; Reddel, R.R.; Deans, A.J.; Pickett, H.A. The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT). Nat. Commun.,  2019, 10(1), 2252.
[http://dx.doi.org/10.1038/s41467-019-10180-6] [PMID: 31138797] 
[23] 
Silva, B.; Pentz, R.; Figueira, A.M.; Arora, R.; Lee, Y.W.; Hodson, C.; Wischnewski, H.; Deans, A.J.; Azzalin, C.M. FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops. Nat. Commun.,  2019, 10(1), 2253.
[http://dx.doi.org/10.1038/s41467-019-10179-z] [PMID: 31138795] 
[24] 
Yeager, T.R.; Neumann, A.A.; Englezou, A.; Huschtscha, L.I.; Noble, J.R.; Reddel, R.R. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res.,  1999, 59(17), 4175-4179.
[PMID: 10485449] 
[25] 
Zhao, Y.M.; Li, J.Y.; Lan, J.P.; Lai, X.Y.; Luo, Y.; Sun, J.; Yu, J.; Zhu, Y.Y.; Zeng, F.F.; Zhou, Q.; Huang, H. Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells. Biochem. Biophys. Res. Commun.,  2008, 369(4), 1114-1119.
[http://dx.doi.org/10.1016/j.bbrc.2008.03.011] [PMID: 18339310] 
[26] 
Henson, J.D.; Reddel, R.R. Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Lett.,  2010, 584(17), 3800-3811.
[http://dx.doi.org/10.1016/j.febslet.2010.06.009] [PMID: 20542034] 
[27] 
Fasching, C.L.; Neumann, A.A.; Muntoni, A.; Yeager, T.R.; Reddel, R.R. DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA. Cancer Res.,  2007, 67(15), 7072-7077.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1556] [PMID: 17652140] 
[28] 
Jiang, W.Q.; Ringertz, N. Altered distribution of the promyelocytic leukemia-associated protein is associated with cellular senescence. Cell Growth Differ.,  1997, 8(5), 513-522.
[PMID: 9213441] 
[29] 
Cerone, M.A.; Autexier, C.; Londoño-Vallejo, J.A.; Bacchetti, S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene,  2005, 24(53), 7893-7901.
[http://dx.doi.org/10.1038/sj.onc.1208934] [PMID: 16116482] 
[30] 
Londoño-Vallejo, J.A.; Der-Sarkissian, H.; Cazes, L.; Bacchetti, S.; Reddel, R.R. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res.,  2004, 64(7), 2324-2327.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-4035] [PMID: 15059879] 
[31] 
Aymard, F.; Bugler, B.; Schmidt, C.K.; Guillou, E.; Caron, P.; Briois, S.; Iacovoni, J.S.; Daburon, V.; Miller, K.M.; Jackson, S.P.; Legube, G. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol.,  2014, 21(4), 366-374.
[http://dx.doi.org/10.1038/nsmb.2796] [PMID: 24658350] 
[32] 
Zhdanova, N.S.; Rubtsov, N.B. Telomere recombination in normal mammalian cells. Genetika,  2016, 52(1), 14-23.
[PMID: 27183789] 
[33] 
Dunham, M.A.; Neumann, A.A.; Fasching, C.L.; Reddel, R.R. Telomere maintenance by recombination in human cells. Nat. Genet.,  2000, 26(4), 447-450.
[http://dx.doi.org/10.1038/82586] [PMID: 11101843] 
[34] 
Cesare, A.J.; Griffith, J.D. Telomeric DNA in ALT cells is characterized by free telomeric circles and heterogeneous t-loops. Mol. Cell. Biol.,  2004, 24(22), 9948-9957.
[http://dx.doi.org/10.1128/MCB.24.22.9948-9957.2004] [PMID: 15509797] 
[35] 
Wang, R.C.; Smogorzewska, A.; de Lange, T. Homologous recombination generates T-loop-sized deletions at human telomeres. Cell,  2004, 119(3), 355-368.
[http://dx.doi.org/10.1016/j.cell.2004.10.011] [PMID: 15507207] 
[36] 
Henson, J.D.; Cao, Y.; Huschtscha, L.I.; Chang, A.C.; Au, A.Y.; Pickett, H.A.; Reddel, R.R. DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat. Biotechnol.,  2009, 27(12), 1181-1185.
[http://dx.doi.org/10.1038/nbt.1587] [PMID: 19935656] 
[37] 
Henson, J.D.; Lau, L.M.; Koch, S.; Martin La Rotta, N.; Dagg, R.A.; Reddel, R.R. The C-Circle Assay for alternative-lengthening-of-telomeres activity. Methods,  2017, 114, 74-84.
[http://dx.doi.org/10.1016/j.ymeth.2016.08.016] [PMID: 27595911] 
[38] 
Samassekou, O.; Malina, A.; Hébert, J.; Yan, J. Presence of alternative lengthening of telomeres associated circular extrachromosome telomere repeats in primary leukemia cells of chronic myeloid leukemia. J. Hematol. Oncol.,  2013, 6, 26.
[http://dx.doi.org/10.1186/1756-8722-6-26] [PMID: 23547895] 
[39] 
Lau, L.M.; Dagg, R.A.; Henson, J.D.; Au, A.Y.; Royds, J.A.; Reddel, R.R. Detection of alternative lengthening of telomeres by telomere quantitative PCR. Nucleic Acids Res.,  2013, 41(2), e34
[http://dx.doi.org/10.1093/nar/gks781] [PMID: 22923525] 
[40] 
Tomaska, L.; Nosek, J.; Kar, A.; Willcox, S.; Griffith, J.D. A new view of the t-loop junction: implications for self-primed telomere extension, expansion of disease-related nucleotide repeat blocks, and telomere evolution. Front. Genet.,  2019, 10, 792.
[http://dx.doi.org/10.3389/fgene.2019.00792] [PMID: 31475042] 
[41] 
Li, F.; Deng, Z.; Zhang, L.; Wu, C.; Jin, Y.; Hwang, I.; Vladimirova, O.; Xu, L.; Yang, L.; Lu, B.; Dheekollu, J.; Li, J.Y.; Feng, H.; Hu, J.; Vakoc, C.R.; Ying, H.; Paik, J.; Lieberman, P.M.; Zheng, H. ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization. EMBO J.,  2019, 38(19), e96659
[http://dx.doi.org/10.15252/embj.201796659] [PMID: 31454099] 
[42] 
Wu, G.; Chen, L.; Liu, W.; Yang, D. Molecular recognition of the hybrid-type G-quadruplexes in human telomeres. Molecules,  2019, 24(8), E1578
[http://dx.doi.org/10.3390/molecules24081578] [PMID: 31013622] 
[43] 
Lee, M.; Teber, E.T.; Holmes, O.; Nones, K.; Patch, A.M.; Dagg, R.A.; Lau, L.M.S.; Lee, J.H.; Napier, C.E.; Arthur, J.W.; Grimmond, S.M.; Hayward, N.K.; Johansson, P.A.; Mann, G.J.; Scolyer, R.A.; Wilmott, J.S.; Reddel, R.R.; Pearson, J.V.; Waddell, N.; Pickett, H.A. Telomere sequence content can be used to determine ALT activity in tumours. Nucleic Acids Res.,  2018, 46(10), 4903-4918.
[http://dx.doi.org/10.1093/nar/gky297] [PMID: 29718321] 
[44] 
Nabetani, A.; Ishikawa, F. Unusual telomeric DNAs in human telomerase-negative immortalized cells. Mol. Cell. Biol.,  2009, 29(3), 703-713.
[http://dx.doi.org/10.1128/MCB.00603-08] [PMID: 19015236] 
[45] 
Xu, B.; Peng, M.; Song, Q. The co-expression of telomerase and ALT pathway in human breast cancer tissues. Tumour Biol.,  2014, 35(5), 4087-4093.
[http://dx.doi.org/10.1007/s13277-013-1534-0] [PMID: 24375252] 
[46] 
Chen, Y.J.; Hakin-Smith, V.; Teo, M.; Xinarianos, G.E.; Jellinek, D.A.; Carroll, T.; McDowell, D.; MacFarlane, M.R.; Boet, R.; Baguley, B.C.; Braithwaite, A.W.; Reddel, R.R.; Royds, J.A. Association of mutant TP53 with alternative lengthening of telomeres and favorable prognosis in glioma. Cancer Res.,  2006, 66(13), 6473-6476.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0910] [PMID: 16818615] 
[47] 
Pal, D.; Sharma, U.; Khajuria, R.; Singh, S.K.; Kakkar, N.; Prasad, R. Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers. Gene,  2015, 562(2), 145-151.
[http://dx.doi.org/10.1016/j.gene.2015.02.079] [PMID: 25769384] 
[48] 
Hakin-Smith, V.; Jellinek, D.A.; Levy, D.; Carroll, T.; Teo, M.; Timperley, W.R.; McKay, M.J.; Reddel, R.R.; Royds, J.A. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet,  2003, 361(9360), 836-838.
[http://dx.doi.org/10.1016/S0140-6736(03)12681-5] [PMID: 12642053] 
[49] 
Dilley, R.L.; Greenberg, R.A. Alternative telomere maintenance and cancer. Trends Cancer,  2015, 1(2), 145-156.
[http://dx.doi.org/10.1016/j.trecan.2015.07.007] [PMID: 26645051] 
[50] 
Pickett, H.A.; Reddel, R.R. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat. Struct. Mol. Biol.,  2015, 22(11), 875-880.
[http://dx.doi.org/10.1038/nsmb.3106] [PMID: 26581522] 
[51] 
Matsuo, T.; Shimose, S.; Kubo, T.; Fujimori, J.; Yasunaga, Y.; Ochi, M. Telomeres and telomerase in sarcomas. Anticancer Res.,  2009, 29(10), 3833-3836.
[PMID: 19846916] 
[52] 
Liau, J.Y.; Lee, J.C.; Tsai, J.H.; Yang, C.Y.; Liu, T.L.; Ke, Z.L.; Hsu, H.H.; Jeng, Y.M. Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas. Mod. Pathol.,  2015, 28(12), 1545-1554.
[http://dx.doi.org/10.1038/modpathol.2015.114] [PMID: 26428317] 
[53] 
Lawlor, R.T.; Veronese, N.; Pea, A.; Nottegar, A.; Smith, L.; Pilati, C.; Demurtas, J.; Fassan, M.; Cheng, L.; Luchini, C. Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis. BMC Cancer,  2019, 19(1), 232.
[http://dx.doi.org/10.1186/s12885-019-5424-8] [PMID: 30871494] 
[54] 
Zhou, J.; Reddy, M.V.; Wilson, B.K.J.; Blair, D.A.; Taha, A.; Frampton, C.M.; Eiholzer, R.A.; Gan, P.Y.C.; Ziad, F.; Thotathil, Z.; Kirs, S.; Hung, N.A.; Royds, J.A.; Slatter, T.L. MR imaging characteristics associate with tumor-associated macrophages in glioblastoma and provide an improved signature for survival prognostication. AJNR Am. J. Neuroradiol.,  2018, 39(2), 252-259.
[http://dx.doi.org/10.3174/ajnr.A5441] [PMID: 29191871] 
[55] 
Durant, S.T. Telomerase-independent paths to immortality in predictable cancer subtypes. J. Cancer,  2012, 3, 67-82.
[http://dx.doi.org/10.7150/jca.3965] [PMID: 22315652] 
[56] 
Ohba, S.; Hirose, Y. Association between mutant IDHs and tumorigenesis in gliomas. Med. Mol. Morphol.,  2018, 51(4), 194-198.
[http://dx.doi.org/10.1007/s00795-018-0189-8] [PMID: 29633022] 
[57] 
Nguyen, D.N.; Heaphy, C.M.; de Wilde, R.F.; Orr, B.A.; Odia, Y.; Eberhart, C.G.; Meeker, A.K.; Rodriguez, F.J. Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol.,  2013, 23(3), 237-243.
[http://dx.doi.org/10.1111/j.1750-3639.2012.00630.x] [PMID: 22928601] 
[58] 
Cai, J.; Yang, P.; Zhang, C.; Zhang, W.; Liu, Y.; Bao, Z.; Liu, X.; Du, W.; Wang, H.; Jiang, T.; Jiang, C. ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples samples. Oncotarget,  2014, 5(9), 2551-2561.
[http://dx.doi.org/10.18632/oncotarget.1838] [PMID: 24810474] 
[59] 
Kannan, K.; Inagaki, A.; Silber, J.; Gorovets, D.; Zhang, J.; Kastenhuber, E.R.; Heguy, A.; Petrini, J.H.; Chan, T.A.; Huse, J.T. Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget,  2012, 3(10), 1194-1203.
[http://dx.doi.org/10.18632/oncotarget.689] [PMID: 23104868] 
[60] 
Jiao, Y.; Killela, P.J.; Reitman, Z.J.; Rasheed, A.B.; Heaphy, C.M.; de Wilde, R.F.; Rodriguez, F.J.; Rosemberg, S.; Oba-Shinjo, S.M.; Nagahashi Marie, S.K.; Bettegowda, C.; Agrawal, N.; Lipp, E.; Pirozzi, C.; Lopez, G.; He, Y.; Friedman, H.; Friedman, A.H.; Riggins, G.J.; Holdhoff, M.; Burger, P.; McLendon, R.; Bigner, D.D.; Vogelstein, B.; Meeker, A.K.; Kinzler, K.W.; Papadopoulos, N.; Diaz, L.A.; Yan, H. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget,  2012, 3(7), 709-722.
[http://dx.doi.org/10.18632/oncotarget.588] [PMID: 22869205] 
[61] 
Abedalthagafi, M.; Phillips, J.J.; Kim, G.E.; Mueller, S.; Haas-Kogen, D.A.; Marshall, R.E.; Croul, S.E.; Santi, M.R.; Cheng, J.; Zhou, S.; Sullivan, L.M.; Martinez-Lage, M.; Judkins, A.R.; Perry, A. The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas. Mod. Pathol.,  2013, 26(11), 1425-1432.
[http://dx.doi.org/10.1038/modpathol.2013.90] [PMID: 23765250] 
[62] 
Wiestler, B.; Capper, D.; Holland-Letz, T.; Korshunov, A.; von Deimling, A.; Pfister, S.M.; Platten, M.; Weller, M.; Wick, W. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol.,  2013, 126(3), 443-451.
[http://dx.doi.org/10.1007/s00401-013-1156-z] [PMID: 23904111] 
[63] 
Mangerel, J.; Price, A.; Castelo-Branco, P.; Brzezinski, J.; Buczkowicz, P.; Rakopoulos, P.; Merino, D.; Baskin, B.; Wasserman, J.; Mistry, M.; Barszczyk, M.; Picard, D.; Mack, S.; Remke, M.; Starkman, H.; Elizabeth, C.; Zhang, C.; Alon, N.; Lees, J.; Andrulis, I.L.; Wunder, J.S.; Jabado, N.; Johnston, D.L.; Rutka, J.T.; Dirks, P.B.; Bouffet, E.; Taylor, M.D.; Huang, A.; Malkin, D.; Hawkins, C.; Tabori, U. Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors. Acta Neuropathol.,  2014, 128(6), 853-862.
[http://dx.doi.org/10.1007/s00401-014-1348-1] [PMID: 25315281] 
[64] 
Minasi, S.; Baldi, C.; Pietsch, T.; Donofrio, V.; Pollo, B.; Antonelli, M.; Massimino, M.; Giangaspero, F.; Buttarelli, F.R. Telomere elongation via alternative lengthening of telomeres (ALT) and telomerase activation in primary metastatic medulloblastoma of childhood. J. Neurooncol.,  2019, 142(3), 435-444.
[http://dx.doi.org/10.1007/s11060-019-03127-w] [PMID: 30830680] 
[65] 
Henson, J.D.; Hannay, J.A.; McCarthy, S.W.; Royds, J.A.; Yeager, T.R.; Robinson, R.A.; Wharton, S.B.; Jellinek, D.A.; Arbuckle, S.M.; Yoo, J.; Robinson, B.G.; Learoyd, D.L.; Stalley, P.D.; Bonar, S.F.; Yu, D.; Pollock, R.E.; Reddel, R.R. A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin. Cancer Res.,  2005, 11(1), 217-225.
[PMID: 15671549] 
[66] 
McDonald, K.L.; McDonnell, J.; Muntoni, A.; Henson, J.D.; Hegi, M.E.; von Deimling, A.; Wheeler, H.R.; Cook, R.J.; Biggs, M.T.; Little, N.S.; Robinson, B.G.; Reddel, R.R.; Royds, J.A. Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival. J. Neuropathol. Exp. Neurol.,  2010, 69(7), 729-736.
[http://dx.doi.org/10.1097/NEN.0b013e3181e576cf] [PMID: 20535033] 
[67] 
La Torre, D.; Aguennouz, M.; Conti, A.; Giusa, M.; Raffa, G.; Abbritti, R.V.; Germano’, A.; Angileri, F.F. Potential clinical role of telomere length in human glioblastoma. Transl. Med. UniSa,  2011, 1, 243-270.
[PMID: 23905037] 
[68] 
Fogli, A.; Demattei, M.V.; Corset, L.; Vaurs-Barrière, C.; Chautard, E.; Biau, J.; Kémény, J.L.; Godfraind, C.; Pereira, B.; Khalil, T.; Grandin, N.; Arnaud, P.; Charbonneau, M.; Verrelle, P. Detection of the alternative lengthening of telomeres pathway in malignant gliomas for improved molecular diagnosis. J. Neurooncol.,  2017, 135(2), 381-390.
[http://dx.doi.org/10.1007/s11060-017-2585-7] [PMID: 28755323] 
[69] 
Sampl, S.; Pramhas, S.; Stern, C.; Preusser, M.; Marosi, C.; Holzmann, K. Expression of telomeres in astrocytoma WHO grade 2 to 4: TERRA level correlates with telomere length, telomerase activity, and advanced clinical grade. Transl. Oncol.,  2012, 5(1), 56-65.
[http://dx.doi.org/10.1593/tlo.11202] [PMID: 22348177] 
[70] 
Rodriguez, F.J.; Graham, M.K.; Brosnan-Cashman, J.A.; Barber, J.R.; Davis, C.; Vizcaino, M.A.; Palsgrove, D.N.; Giannini, C.; Pekmezci, M.; Dahiya, S.; Gokden, M.; Noë, M.; Wood, L.D.; Pratilas, C.A.; Morris, C.D.; Belzberg, A.; Blakeley, J.; Heaphy, C.M. Telomere alterations in neurofibromatosis type 1-associated solid tumors. Acta Neuropathol. Commun.,  2019, 7(1), 139.
[http://dx.doi.org/10.1186/s40478-019-0792-5] [PMID: 31462295] 
[71] 
Cesare, A.J.; Kaul, Z.; Cohen, S.B.; Napier, C.E.; Pickett, H.A.; Neumann, A.A.; Reddel, R.R. Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions. Nat. Struct. Mol. Biol.,  2009, 16(12), 1244-1251.
[http://dx.doi.org/10.1038/nsmb.1725] [PMID: 19935685] 
[72] 
Lee, J.; Solomon, D.A.; Tihan, T. The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children. J. Neurooncol.,  2017, 132(1), 1-11.
[http://dx.doi.org/10.1007/s11060-016-2349-9] [PMID: 28064387] 
[73] 
Rodriguez, F.J.; Brosnan-Cashman, J.A.; Allen, S.J.; Vizcaino, M.A.; Giannini, C.; Camelo-Piragua, S.; Webb, M.; Matsushita, M.; Wadhwani, N.; Tabbarah, A.; Hamideh, D.; Jiang, L.; Chen, L.; Arvanitis, L.D.; Alnajar, H.H.; Barber, J.R.; Rodríguez-Velasco, A.; Orr, B.; Heaphy, C.M. Alternative lengthening of telomeres, ATRX loss and H3-K27M mutations in histologically defined pilocytic astrocytoma with anaplasia. Brain Pathol.,  2019, 29(1), 126-140.
[http://dx.doi.org/10.1111/bpa.12646] [PMID: 30192422] 
[74] 
Naderlinger, E.; Holzmann, K. Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas. Genes (Basel),  2017, 8(5), 145.
[http://dx.doi.org/10.3390/genes8050145] [PMID: 28513547] 
[75] 
Silvestre, D.C.; Pineda, J.R.; Hoffschir, F.; Studler, J.M.; Mouthon, M.A.; Pflumio, F.; Junier, M.P.; Chneiweiss, H.; Boussin, F.D. Alternative lengthening of telomeres in human glioma stem cells. Stem Cells,  2011, 29(3), 440-451.
[http://dx.doi.org/10.1002/stem.600] [PMID: 21425407] 
[76] 
Hung, N.A.; Eiholzer, R.A.; Kirs, S.; Zhou, J.; Ward-Hartstonge, K.; Wiles, A.K.; Frampton, C.M.; Taha, A.; Royds, J.A.; Slatter, T.L. Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma. Mod. Pathol.,  2016, 29(3), 212-226.
[http://dx.doi.org/10.1038/modpathol.2015.156] [PMID: 26769142] 
[77] 
Hung, N.; Chen, Y.J.; Taha, A.; Olivecrona, M.; Boet, R.; Wiles, A.; Warr, T.; Shaw, A.; Eiholzer, R.; Baguley, B.C.; Eccles, M.R.; Braithwaite, A.W.; Macfarlane, M.; Royds, J.A.; Slatter, T. Increased paired box transcription factor 8 has a survival function in glioma. BMC Cancer,  2014, 14(1), 159.
[http://dx.doi.org/10.1186/1471-2407-14-159] [PMID: 24602166] 
[78] 
Lundberg, G.; Sehic, D.; Länsberg, J.K.; Øra, I.; Frigyesi, A.; Castel, V.; Navarro, S.; Piqueras, M.; Martinsson, T.; Noguera, R.; Gisselsson, D. Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas. Genes Chromosomes Cancer,  2011, 50(4), 250-262.
[http://dx.doi.org/10.1002/gcc.20850] [PMID: 21319260] 
[79] 
Tabori, U.; Dome, J.S. Telomere biology of pediatric cancer. Cancer Invest.,  2007, 25(3), 197-208.
[http://dx.doi.org/10.1080/07357900701208683] [PMID: 17530490] 
[80] 
Pezzolo, A.; Pistorio, A.; Gambini, C.; Haupt, R.; Ferraro, M.; Erminio, G.; De Bernardi, B.; Garaventa, A.; Pistoia, V. Intratumoral diversity of telomere length in individual neuroblastoma tumors. Oncotarget,  2015, 6(10), 7493-7503.
[http://dx.doi.org/10.18632/oncotarget.2115] [PMID: 25595889] 
[81] 
Onitake, Y.; Hiyama, E.; Kamei, N.; Yamaoka, H.; Sueda, T.; Hiyama, K. Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres. J. Pediatr. Surg.,  2009, 44(12), 2258-2266.
[http://dx.doi.org/10.1016/j.jpedsurg.2009.07.046] [PMID: 20006006] 
[82] 
Peifer, M.; Hertwig, F.; Roels, F.; Dreidax, D.; Gartlgruber, M.; Menon, R.; Krämer, A.; Roncaioli, J.L.; Sand, F.; Heuckmann, J.M.; Ikram, F.; Schmidt, R.; Ackermann, S.; Engesser, A.; Kahlert, Y.; Vogel, W.; Altmüller, J.; Nürnberg, P.; Thierry-Mieg, J.; Thierry-Mieg, D.; Mariappan, A.; Heynck, S.; Mariotti, E.; Henrich, K.O.; Gloeckner, C.; Bosco, G.; Leuschner, I.; Schweiger, M.R.; Savelyeva, L.; Watkins, S.C.; Shao, C.; Bell, E.; Höfer, T.; Achter, V.; Lang, U.; Theissen, J.; Volland, R.; Saadati, M.; Eggert, A.; de Wilde, B.; Berthold, F.; Peng, Z.; Zhao, C.; Shi, L.; Ortmann, M.; Büttner, R.; Perner, S.; Hero, B.; Schramm, A.; Schulte, J.H.; Herrmann, C.; O’Sullivan, R.J.; Westermann, F.; Thomas, R.K.; Fischer, M. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature,  2015, 526(7575), 700-704.
[http://dx.doi.org/10.1038/nature14980] [PMID: 26466568] 
[83] 
Kurihara, S.; Hiyama, E.; Onitake, Y.; Yamaoka, E.; Hiyama, K. Clinical features of ATRX or DAXX mutated neuroblastoma. J. Pediatr. Surg.,  2014, 49(12), 1835-1838.
[http://dx.doi.org/10.1016/j.jpedsurg.2014.09.029] [PMID: 25487495] 
[84] 
Duan, X.F.; Zhao, Q. TERT-mediated and ATRX-mediated Telomere Maintenance and Neuroblastoma. J. Pediatr. Hematol. Oncol.,  2018, 40(1), 1-6.
[http://dx.doi.org/10.1097/MPH.0000000000000840] [PMID: 28452859] 
[85] 
de Wilde, R.F.; Heaphy, C.M.; Maitra, A.; Meeker, A.K.; Edil, B.H.; Wolfgang, C.L.; Vriens, M.R. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Modern Pathology 25.7,  2012, 25(7), 1033-1039.
[http://dx.doi.org/10.1038/modpathol.2012.53] 
[86] 
Marinoni, I.; Kurrer, A.S.; Vassella, E.; Dettmer, M.; Rudolph, T.; Banz, V.; Hunger, F.; Pasquinelli, S.; Speel, E.J.; Perren, A. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology,  2014, 146(2), 453-60.e5.
[http://dx.doi.org/10.1053/j.gastro.2013.10.020] [PMID: 24148618] 
[87] 
Kim, H.S.; Lee, H.S.; Nam, K.H.; Choi, J.; Kim, W.H. Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors. Anticancer Res.,  2015, 35(6), 3501-3510.
[PMID: 26026117] 
[88] 
Kim, J.Y.; Brosnan-Cashman, J.A.; An, S.; Kim, S.J.; Song, K.B.; Kim, M.S.; Kim, M.J.; Hwang, D.W.; Meeker, A.K.; Yu, E.; Kim, S.C.; Hruban, R.H.; Heaphy, C.M.; Hong, S.M. Alternative lengthening of telomeres in primary pancreatic neuroendocrine tumors is associated with aggressive clinical behavior and poor survival. Clin. Cancer Res.,  2017, 23(6), 1598-1606.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1147] [PMID: 27663587] 
[89] 
Singhi, A.D.; Liu, T.C.; Roncaioli, J.L.; Cao, D.; Zeh, H.J.; Zureikat, A.H.; Tsung, A.; Marsh, J.W.; Lee, K.K.; Hogg, M.E.; Bahary, N.; Brand, R.E.; McGrath, K.M.; Slivka, A.; Cressman, K.L.; Fuhrer, K.; O’Sullivan, R.J. Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors. Clin. Cancer Res.,  2017, 23(2), 600-609.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1113] [PMID: 27407094] 
[90] 
VandenBussche, C.J.; Allison, D.B.; Graham, M.K.; Charu, V.; Lennon, A.M.; Wolfgang, C.L.; Hruban, R.H.; Heaphy, C.M. Alternative lengthening of telomeres and ATRX/DAXX loss can be reliably detected in FNAs of pancreatic neuroendocrine tumors. Cancer Cytopathol.,  2017, 125(7), 544-551.
[http://dx.doi.org/10.1002/cncy.21857] [PMID: 28371511] 
[91] 
Cejas, P.; Drier, Y.; Dreijerink, K.M.A.; Brosens, L.A.A.; Deshpande, V.; Epstein, C.B.; Conemans, E.B.; Morsink, F.H.M.; Graham, M.K.; Valk, G.D.; Vriens, M.R.; Castillo, C.F.; Ferrone, C.R.; Adar, T.; Bowden, M.; Whitton, H.J.; Da Silva, A.; Font-Tello, A.; Long, H.W.; Gaskell, E.; Shoresh, N.; Heaphy, C.M.; Sicinska, E.; Kulke, M.H.; Chung, D.C.; Bernstein, B.E.; Shivdasani, R.A. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nat. Med.,  2019, 25(8), 1260-1265.
[http://dx.doi.org/10.1038/s41591-019-0493-4] [PMID: 31263286] 
[92] 
Mafficini, A.; Scarpa, A. Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium. J. Endocrinol.,  2018, 236(3), R161-R167.
[http://dx.doi.org/10.1530/JOE-17-0560] [PMID: 29321190] 
[93] 
Dogeas, E.; Karagkounis, G.; Heaphy, C.M.; Hirose, K.; Pawlik, T.M.; Wolfgang, C.L.; Meeker, A.; Hruban, R.H.; Cameron, J.L.; Choti, M.A. Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor liver metastases. J. Am. Coll. Surg.,  2014, 218(4), 628-635.
[http://dx.doi.org/10.1016/j.jamcollsurg.2014.01.001] [PMID: 24655849] 
[94] 
Pea, A.; Yu, J.; Marchionni, L.; Noe, M.; Luchini, C.; Pulvirenti, A.; de Wilde, R.F.; Brosens, L.A.; Rezaee, N.; Javed, A.; Gobbo, S.; Regi, P.; Salvia, R.; Bassi, C.; He, J.; Weiss, M.J.; Cameron, J.L.; Offerhaus, G.J.A.; Hruban, R.H.; Lawlor, R.T.; Scarpa, A.; Heaphy, C.M.; Wood, L.D.; Wolfgang, C.L. Genetic analysis of small well-differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases. Ann. Surg.,  2018, 20(20), 1-8.
[http://dx.doi.org/10.1097/SLA.0000000000003022] [PMID: 30339629] 
[95] 
Zaffaroni, N.; Villa, R.; Pastorino, U.; Cirincione, R.; Incarbone, M.; Alloisio, M.; Curto, M.; Pilotti, S.; Daidone, M.G. Lack of telomerase activity in lung carcinoids is dependent on human telomerase reverse transcriptase transcription and alternative splicing and is associated with long telomeres. Clin. Cancer Res.,  2005, 11(8), 2832-2839.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1293] [PMID: 15837730] 
[96] 
Cairney, C.J.; Hoare, S.F.; Daidone, M.G.; Zaffaroni, N.; Keith, W.N. High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma. Br. J. Cancer,  2008, 98(8), 1467-1474.
[http://dx.doi.org/10.1038/sj.bjc.6604328] [PMID: 18414473] 
[97] 
Lee, J.C.; Jeng, Y.M.; Liau, J.Y.; Tsai, J.H.; Hsu, H.H.; Yang, C.Y. Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas. Mod. Pathol.,  2015, 28(8), 1064-1073.
[http://dx.doi.org/10.1038/modpathol.2015.67] [PMID: 26022452] 
[98] 
Costa, A.; Daidone, M.G.; Daprai, L.; Villa, R.; Cantù, S.; Pilotti, S.; Mariani, L.; Gronchi, A.; Henson, J.D.; Reddel, R.R.; Zaffaroni, N. Telomere maintenance mechanisms in liposarcomas: association with histologic subtypes and disease progression. Cancer Res.,  2006, 66(17), 8918-8924.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0273] [PMID: 16951210] 
[99] 
Jeyapalan, J.N.; Mendez-Bermudez, A.; Zaffaroni, N.; Dubrova, Y.E.; Royle, N.J. Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies. Int. J. Cancer,  2008, 122(11), 2414-2421.
[http://dx.doi.org/10.1002/ijc.23412] [PMID: 18311780] 
[100] 
Johnson, J.E.; Varkonyi, R.J.; Schwalm, J.; Cragle, R.; Klein-Szanto, A.; Patchefsky, A.; Cukierman, E.; von Mehren, M.; Broccoli, D. Multiple mechanisms of telomere maintenance exist in liposarcomas. Clin. Cancer Res.,  2005, 11(15), 5347-5355.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-0684] [PMID: 16061847] 
[101] 
Venturini, L.; Motta, R.; Gronchi, A.; Daidone, M.; Zaffaroni, N. Prognostic relevance of ALT-associated markers in liposarcoma: a comparative analysis. BMC Cancer,  2010, 10, 254.
[http://dx.doi.org/10.1186/1471-2407-10-254] [PMID: 20525266] 
[102] 
Heaphy, C.M.; de Wilde, R.F.; Jiao, Y.; Klein, A.P.; Edil, B.H.; Shi, C.; Bettegowda, C.; Rodriguez, F.J.; Eberhart, C.G.; Hebbar, S.; Offerhaus, G.J.; McLendon, R.; Rasheed, B.A.; He, Y.; Yan, H.; Bigner, D.D.; Oba-Shinjo, S.M.; Marie, S.K.; Riggins, G.J.; Kinzler, K.W.; Vogelstein, B.; Hruban, R.H.; Maitra, A.; Papadopoulos, N.; Meeker, A.K. Altered telomeres in tumors with ATRX and DAXX mutations. Science,  2011, 333(6041), 425.
[http://dx.doi.org/10.1126/science.1207313] [PMID: 21719641] 
[103] 
Heaphy, C.M.; Subhawong, A.P.; Hong, S.M.; Goggins, M.G.; Montgomery, E.A.; Gabrielson, E.; Netto, G.J.; Epstein, J.I.; Lotan, T.L.; Westra, W.H.; Shih, IeM.; Iacobuzio-Donahue, C.A.; Maitra, A.; Li, Q.K.; Eberhart, C.G.; Taube, J.M.; Rakheja, D.; Kurman, R.J.; Wu, T.C.; Roden, R.B.; Argani, P.; De Marzo, A.M.; Terracciano, L.; Torbenson, M.; Meeker, A.K. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am. J. Pathol.,  2011, 179(4), 1608-1615.
[http://dx.doi.org/10.1016/j.ajpath.2011.06.018] [PMID: 21888887] 
[104] 
Ulaner, G.A.; Hoffman, A.R.; Otero, J.; Huang, H.Y.; Zhao, Z.; Mazumdar, M.; Gorlick, R.; Meyers, P.; Healey, J.H.; 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(2), 155-162.
[http://dx.doi.org/10.1002/gcc.20074] [PMID: 15287028] 
[105] 
Ulaner, G.A.; Huang, H.Y.; Otero, J.; Zhao, Z.; Ben-Porat, L.; Satagopan, J.M.; Gorlick, R.; Meyers, P.; Healey, J.H.; Huvos, A.G.; Hoffman, A.R.; Ladanyi, M. Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma. Cancer Res.,  2003, 63(8), 1759-1763.
[PMID: 12702558] 
[106] 
Sanders, R.P.; Drissi, R.; Billups, C.A.; Daw, N.C.; Valentine, M.B.; Dome, J.S. Telomerase expression predicts unfavorable outcome in osteosarcoma. J. Clin. Oncol.,  2004, 22(18), 3790-3797.
[http://dx.doi.org/10.1200/JCO.2004.03.043] [PMID: 15365076] 
[107] 
Sotillo-Piñeiro, E.; Sierrasesúmaga, L.; Patiñno-García, A. Telomerase activity and telomere length in primary and metastatic tumors from pediatric bone cancer patients. Pediatr. Res.,  2004, 55(2), 231-235.
[http://dx.doi.org/10.1203/01.PDR.0000102455.36737.3C] [PMID: 14630995] 
[108] 
Matsuo, T.; Shimose, S.; Kubo, T.; Fujimori, J.; Yasunaga, Y.; Ochi, M. Alternative lengthening of telomeres as a prognostic factor in malignant fibrous histiocytomas of bone. Anticancer Res.,  2010, 30(12), 4959-4962.
[PMID: 21187476] 
[109] 
Allegra, A.; Innao, V.; Penna, G.; Gerace, D.; Allegra, A.G.; Musolino, C. Telomerase and telomere biology in hematological diseases: A new therapeutic target. Leuk. Res.,  2017, 56, 60-74.
[http://dx.doi.org/10.1016/j.leukres.2017.02.002] [PMID: 28196338] 
[110] 
Kishtagari, A.; Watts, J. Biological and clinical implications of telomere dysfunction in myeloid malignancies. Ther. Adv. Hematol.,  2017, 8(11), 317-326.
[http://dx.doi.org/10.1177/2040620717731549] [PMID: 29093807] 
[111] 
Medves, S.; Auchter, M.; Chambeau, L.; Gazzo, S.; Poncet, D.; Grangier, B.; Verney, A.; Moussay, E.; Ammerlaan, W.; Brisou, G.; Morjani, H.; Géli, V.; Palissot, V.; Berchem, G.; Salles, G.; Wenner, T. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells. Br. J. Haematol.,  2016, 174(1), 57-70.
[http://dx.doi.org/10.1111/bjh.13995] [PMID: 26970083] 
[112] 
M’kacher, R.; Cuceu, C.; Al Jawhari, M.; Morat, L.; Frenzel, M.; Shim, G.; Lenain, A.; Hempel, W.M.; Junker, S.; Girinsky, T.; Colicchio, B.; Dieterlen, A.; Heidingsfelder, L.; Borie, C.; Oudrhiri, N.; Bennaceur-Griscelli, A.; Moralès, O.; Renaud, S.; Van de Wyngaert, Z.; Jeandidier, E.; Delhem, N.; Carde, P. The transition between telomerase and alt mechanisms in hodgkin lymphoma and its predictive value in clinical Outcomes. Cancers (Basel),  2018, 10(6), 169.
[http://dx.doi.org/10.3390/cancers10060169] [PMID: 29848986] 
[113] 
Slatter, T.L.; Hsia, H.; Samaranayaka, A.; Sykes, P.; Clow, W.B.; Devenish, C.J.; Sutton, T.; Royds, J.A.; Ip, P.P.; Cheung, A.N.; Hung, N.A. Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma. J. Pathol. Clin. Res.,  2015, 1(2), 95-105.
[http://dx.doi.org/10.1002/cjp2.11] [PMID: 27499896] 
[114] 
Liau, J.Y.; Tsai, J.H.; Jeng, Y.M.; Lee, J.C.; Hsu, H.H.; Yang, C.Y. Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome. Am. J. Surg. Pathol.,  2015, 39(2), 236-244.
[http://dx.doi.org/10.1097/PAS.0000000000000324] [PMID: 25229770] 
[115] 
Mäkinen, N.; Aavikko, M.; Heikkinen, T.; Taipale, M.; Taipale, J.; Koivisto-Korander, R.; Bützow, R.; Vahteristo, P. Exome sequencing of uterine leiomyosarcomas identifies frequent mutations in TP53, ATRX, and MED12. PLoS Genet.,  2016, 12(2), e1005850
[http://dx.doi.org/10.1371/journal.pgen.1005850] [PMID: 26891131] 
[116] 
Chudasama, P.; Mughal, S.S.; Sanders, M.A.; Hübschmann, D.; Chung, I.; Deeg, K.I.; Wong, S.H.; Rabe, S.; Hlevnjak, M.; Zapatka, M.; Ernst, A.; Kleinheinz, K.; Schlesner, M.; Sieverling, L.; Klink, B.; Schröck, E.; Hoogenboezem, R.M.; Kasper, B.; Heilig, C.E.; Egerer, G.; Wolf, S.; von Kalle, C.; Eils, R.; Stenzinger, A.; Weichert, W.; Glimm, H.; Gröschel, S.; Kopp, H.G.; Omlor, G.; Lehner, B.; Bauer, S.; Schimmack, S.; Ulrich, A.; Mechtersheimer, G.; Rippe, K.; Brors, B.; Hutter, B.; Renner, M.; Hohenberger, P.; Scholl, C.; Fröhling, S. Integrative genomic and transcriptomic analysis of leiomyosarcoma. Nat. Commun.,  2018, 9(1), 144.
[http://dx.doi.org/10.1038/s41467-017-02602-0] [PMID: 29321523] 
[117] 
Lee, Y.K.; Park, N.H.; Lee, H. Prognostic value of alternative lengthening of telomeres-associated biomarkers in uterine sarcoma and uterine carcinosarcoma. Int. J. Gynecol. Cancer,  2012, 22(3), 434-441.
[http://dx.doi.org/10.1097/IGC.0b013e31823ca017] [PMID: 22266933] 
[118] 
Ahvenainen, T.V.; Mäkinen, N.M.; von Nandelstadh, P.; Vahteristo, M.E.A.; Pasanen, A.M.; Bützow, R.C.; Vahteristo, P.M. Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas. Cancer,  2018, 124(24), 4650-4656.
[http://dx.doi.org/10.1002/cncr.31754] [PMID: 30423196] 
[119] 
Müller, M.; Heicappell, R.; Krause, H.; Sachsinger, J.; Porsche, C.; Miller, K. Telomerase activity in malignant and benign renal tumors. Eur. Urol.,  1999, 35(3), 249-255.
[http://dx.doi.org/10.1159/000019856] [PMID: 10072629] 
[120] 
Venturini, L.; Daidone, M.G.; Motta, R.; Collini, P.; Spreafico, F.; Terenziani, M.; Piva, L.; Radice, P.; Perotti, D.; Zaffaroni, N. Telomere maintenance in Wilms tumors: first evidence for the presence of alternative lengthening of telomeres mechanism. Genes Chromosomes Cancer,  2011, 50(10), 823-829.
[http://dx.doi.org/10.1002/gcc.20903] [PMID: 21769957] 
[121] 
Subhawong, A.P.; Heaphy, C.M.; Argani, P.; Konishi, Y.; Kouprina, N.; Nassar, H.; Vang, R.; Meeker, A.K. The alternative lengthening of telomeres phenotype in breast carcinoma is associated with HER-2 overexpression. Mod. Pathol.,  2009, 22(11), 1423-1431.
[http://dx.doi.org/10.1038/modpathol.2009.125] [PMID: 19734843] 
[122] 
Boardman, L.A.; Johnson, R.A.; Viker, K.B.; Hafner, K.A.; Jenkins, R.B.; Riegert-Johnson, D.L.; Smyrk, T.C.; Litzelman, K.; Seo, S.; Gangnon, R.E.; Engelman, C.D.; Rider, D.N.; Vanderboom, R.J.; Thibodeau, S.N.; Petersen, G.M.; Skinner, H.G. Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. PLoS One,  2013, 8(11), e80015
[http://dx.doi.org/10.1371/journal.pone.0080015] [PMID: 24278232] 
[123] 
Druliner, B.R.; Ruan, X.; Johnson, R.; Grill, D.; O’Brien, D.; Lai, T.P.; Rashtak, S.; Felmlee-Devine, D.; Washechek-Aletto, J.; Malykh, A.; Smyrk, T.; Oberg, A.; Liu, H.; Shay, J.W.; Ahlquist, D.A.; Boardman, L.A. Time lapse to colorectal cancer: telomere dynamics define the malignant potential of polyps. Clin. Transl. Gastroenterol.,  2017, 8(4), e88
[http://dx.doi.org/10.1038/ctg.2017.16] [PMID: 28406492] 
[124] 
Else, T.; Giordano, T.J.; Hammer, G.D. Evaluation of telomere length maintenance mechanisms in adrenocortical carcinoma. J. Clin. Endocrinol. Metab.,  2008, 93(4), 1442-1449.
[http://dx.doi.org/10.1210/jc.2007-1840] [PMID: 18198226] 
[125] 
Basu, N.; Skinner, H.G.; Litzelman, K.; Vanderboom, R.; Baichoo, E.; Boardman, L.A. Telomeres and telomere dynamics: relevance to cancers of the GI tract. Expert Rev. Gastroenterol. Hepatol.,  2013, 7(8), 733-748.
[http://dx.doi.org/10.1586/17474124.2013.848790] [PMID: 24161135] 
[126] 
Heeg, S. Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer. Pharm. Genomics Pers. Med.,  2015, 8, 171-180.
[http://dx.doi.org/10.2147/PGPM.S52808] [PMID: 26675332] 
[127] 
Omori, Y.; Nakayama, F.; Li, D.; Kanemitsu, K.; Semba, S.; Ito, A.; Yokozaki, H. Alternative lengthening of telomeres frequently occurs in mismatch repair system-deficient gastric carcinoma. Cancer Sci.,  2009, 100(3), 413-418.
[http://dx.doi.org/10.1111/j.1349-7006.2008.01063.x] [PMID: 19154407] 
[128] 
Ohali, A.; Avigad, S.; Naumov, I.; Goshen, Y.; Ash, S.; Yaniv, I. Different telomere maintenance mechanisms in alveolar and embryonal rhabdomyosarcoma. Genes Chromosomes Cancer,  2008, 47(11), 965-970.
[http://dx.doi.org/10.1002/gcc.20600] [PMID: 18663749] 
[129] 
Job, S.; Draskovic, I.; Burnichon, N.; Buffet, A.; Cros, J.; Lépine, C.; Venisse, A.; Robidel, E.; Verkarre, V.; Meatchi, T.; Sibony, M.; Amar, L.; Bertherat, J.; de Reyniès, A.; Londoño-Vallejo, A.; Favier, J.; Castro-Vega, L.J.; Gimenez-Roqueplo, A.P. Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma. Clin. Cancer Res.,  2019, 25(2), 760-770.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0139] [PMID: 30301828] 
[130] 
Liau, J.Y.; Tsai, J.H.; Yang, C.Y.; Lee, J.C.; Liang, C.W.; Hsu, H.H.; Jeng, Y.M. Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas. Hum. Pathol.,  2015, 46(9), 1360-1366.
[http://dx.doi.org/10.1016/j.humpath.2015.05.019] [PMID: 26190196] 
[131] 
Panse, G.; Chrisinger, J.S.; Leung, C.H.; Ingram, D.R.; Khan, S.; Wani, K.; Lin, H.; Lazar, A.J.; Wang, W.L. Clinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas. Histopathology,  2018, 72(2), 239-247.
[http://dx.doi.org/10.1111/his.13337] [PMID: 28796347] 
[132] 
Villa, R.; Daidone, M.G.; Motta, R.; Venturini, L.; De Marco, C.; Vannelli, A.; Kusamura, S.; Baratti, D.; Deraco, M.; Costa, A.; Reddel, R.R.; Zaffaroni, N. Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma. Clin. Cancer Res.,  2008, 14(13), 4134-4140.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0099] [PMID: 18593991] 
[133] 
Au, A.Y.; Hackl, T.; Yeager, T.R.; Cohen, S.B.; Pass, H.I.; Harris, C.C.; Reddel, R.R. Telomerase activity in pleural malignant mesotheliomas. Lung Cancer,  2011, 73(3), 283-288.
[http://dx.doi.org/10.1016/j.lungcan.2010.12.023] [PMID: 21277646] 
[134] 
Wood, L.D.; Heaphy, C.M.; Daniel, H.D.; Naini, B.V.; Lassman, C.R.; Arroyo, M.R.; Kamel, I.R.; Cosgrove, D.P.; Boitnott, J.K.; Meeker, A.K.; Torbenson, M.S. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod. Pathol.,  2013, 26(12), 1586-1593.
[http://dx.doi.org/10.1038/modpathol.2013.68] [PMID: 23640129] 
[135] 
Wang, N.; Xu, D.; Sofiadis, A.; Höög, A.; Vukojević, V.; Bäckdahl, M.; Zedenius, J.; Larsson, C. Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma. J. Clin. Endocrinol. Metab.,  2014, 99(8), E1571-E1579.
[http://dx.doi.org/10.1210/jc.2014-1158] [PMID: 24758186] 
[136] 
Nasirden, A.; Saito, T.; Fukumura, Y.; Hara, K.; Akaike, K.; Kurisaki-Arakawa, A.; Asahina, M.; Yamashita, A.; Tomomasa, R.; Hayashi, T.; Arakawa, A.; Yao, T. In Japanese patients with papillary thyroid carcinoma, TERT promoter mutation is associated with poor prognosis, in contrast to BRAF V600E mutation. Virchows Arch.,  2016, 469(6), 687-696.
[http://dx.doi.org/10.1007/s00428-016-2027-5] [PMID: 27718012] 
[137] 
Venturini, L.; Daidone, M.G.; Motta, R.; Cimino-Reale, G.; Hoare, S.F.; Gronchi, A.; Folini, M.; Keith, W.N.; Zaffaroni, N. Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: expression and prognostic relevance. Neuro-oncol.,  2012, 14(6), 736-744.
[http://dx.doi.org/10.1093/neuonc/nos083] [PMID: 22516689] 
[138] 
Queisser, A.; Heeg, S.; Thaler, M.; von Werder, A.; Opitz, O.G. Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis. Cancer Genet.,  2013, 206(11), 374-386.
[http://dx.doi.org/10.1016/j.cancergen.2013.10.001] [PMID: 24331919] 
[139] 
Morais, K.D.S.; Arcanjo, D.D.S.; de Faria Lopes, G.P.; da Silva, G.G.; da Mota, T.H.A.; Gabriel, T.R.; Rabello Ramos, D.D.A.; Silva, F.P.; de Oliveira, D.M. Long-term in vitro treatment with telomerase inhibitor MST-312 induces resistance by selecting long telomeres cells. Cell Biochem. Funct.,  2019, 37(4), 273-280.
[http://dx.doi.org/10.1002/cbf.3398] [PMID: 31012504] 
[140] 
Morais, K.S.; Guimarãesb, A.F.R.; Ramos, D.A.R.; Silva, F.P.; de Oliveira, D.M. Long-term exposure to MST-312 leads to telomerase reverse transcriptase overexpression in MCF-7 breast cancer cells. Anticancer Drugs,  2017, 28(7), 750-756.
[http://dx.doi.org/10.1097/CAD.0000000000000508] [PMID: 28520570] 
[141] 
Hu, J.; Hwang, S.S.; Liesa, M.; Gan, B.; Sahin, E.; Jaskelioff, M.; Ding, Z.; Ying, H.; Boutin, A.T.; Zhang, H.; Johnson, S.; Ivanova, E.; Kost-Alimova, M.; Protopopov, A.; Wang, Y.A.; Shirihai, O.S.; Chin, L.; DePinho, R.A. Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell,  2012, 148(4), 651-663.
[http://dx.doi.org/10.1016/j.cell.2011.12.028] [PMID: 22341440] 
[142] 
Gocha, A.R.; Nuovo, G.; Iwenofu, O.H.; Groden, J. Human sarcomas are mosaic for telomerase-dependent and telomerase-independent telomere maintenance mechanisms: implications for telomere-based therapies. Am. J. Pathol.,  2013, 182(1), 41-48.
[http://dx.doi.org/10.1016/j.ajpath.2012.10.001] [PMID: 23260199] 
[143] 
Rodriguez, F.J.; Vizcaino, M.A.; Blakeley, J.; Heaphy, C.M. Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas. Acta Neuropathol.,  2016, 132(5), 761-763.
[http://dx.doi.org/10.1007/s00401-016-1619-0] [PMID: 27650176] 
[144] 
Dorris, K.; Sobo, M.; Onar-Thomas, A.; Panditharatna, E.; Stevenson, C.B.; Gardner, S.L.; Dewire, M.D.; Pierson, C.R.; Olshefski, R.; Rempel, S.A.; Goldman, S.; Miles, L.; Fouladi, M.; Drissi, R. Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas. J. Neurooncol.,  2014, 117(1), 67-76.
[http://dx.doi.org/10.1007/s11060-014-1374-9] [PMID: 24477622] 
Cite As
Current Topics in Medicinal Chemistry

Clinical Relevance of Alternative Lengthening of Telomeres in Cancer

Abstract

Graphical Abstract
