OpenLB
Open Library of Bioscience
Advanced Search
Biogerontology
Apr, 2024;25 (2): 265-278.

Telomere length and cancer risk: finding Goldilocks.

Sharon A Savage
Author Information
  1. Sharon A Savage: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, 6E456, Bethesda, MD, 20892-6772, USA. savagesh@mail.nih.gov. ORCID
PMID: 38109000 DOI: 10.1007/s10522-023-10080-9

Abstract

Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.

Keywords

Cancer Dyskeratosis congenita Genetic variant Polygenic inheritance Polygenic risk score Telomere Telomere biology disorder

References

  1. Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, Danilova L, Applegate CD, Bolton SG, Mohr DW, Brodsky RA, Casella JF, Greider CW, Jackson JB, Armanios M (2018) Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci USA 115(10):E2358–E2365. https://doi.org/10.1073/pnas.1720427115 [DOI: 10.1073/pnas.1720427115]
  2. Allaire P, He J, Mayer J, Moat L, Gerstenberger P, Wilhorn R, Strutz S, Kim DSL, Zeng C, Cox N, Shay JW, Denny J, Bastarache L, Hebbring S (2023) Genetic and clinical determinants of telomere length. HGG Adv 4(3):100201. https://doi.org/10.1016/j.xhgg.2023.100201 [DOI: 10.1016/j.xhgg.2023.100201]
  3. Alter BP, Baerlocher G, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Lansdorp PM (2006) Telomere length measurement by flow-FISH distinguishes dyskeratosis congenita from other bone marrow failure syndromes. Blood 108(11):58A–59A [DOI: 10.1182/blood.V108.11.183.183]
  4. Alter BP, Giri N, Savage SA, Rosenberg PS (2018) Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica 103(1):30–39. https://doi.org/10.3324/haematol.2017.178111 [DOI: 10.3324/haematol.2017.178111]
  5. Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, Gartside M, Quesada V, Johansson P, Palmer JM, Ramsay AJ, Zhang X, Jones K, Symmons J, Holland EA, Schmid H, Bonazzi V, Woods S, Dutton-Regester K, Stark MS, Snowden H, van Doorn R, Montgomery GW, Martin NG, Keane TM, López-Otín C, Gerdes A-M, Olsson H, Ingvar C, Borg Å, Gruis NA, Trent JM, Jönsson DG, Bishop T, Mann GJ, Newton-Bishop JA, Brown KM, Adams DJ, Hayward NK (2015) Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst 107(2):408. https://doi.org/10.1093/jnci/dju408 [DOI: 10.1093/jnci/dju408]
  6. Armstrong E, Boonekamp J (2023) Does oxidative stress shorten telomeres in vivo? A meta-analysis. Ageing Res Rev 85:101854. https://doi.org/10.1016/j.arr.2023.101854 [DOI: 10.1016/j.arr.2023.101854]
  7. Aubert G, Hills M, Lansdorp PM (2012) Telomere length measurement—Caveats and a critical assessment of the available technologies and tools. Mutat Res 730(1):59–67 [DOI: 10.1016/j.mrfmmm.2011.04.003]
  8. Aviv A, Shay JW (2018) Reflections on telomere dynamics and ageing-related diseases in humans. Philos Trans R Soc Lond B Biol Sci 373(1741):20160436. https://doi.org/10.1098/rstb.2016.0436 [DOI: 10.1098/rstb.2016.0436]
  9. Aviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E (2011) Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR. Nucleic Acids Res 39(20):e134. https://doi.org/10.1093/nar/gkr634 [DOI: 10.1093/nar/gkr634]
  10. Aviv A, Anderson JJ, Shay JW (2017) Mutations, cancer and the telomere length paradox. Trends Cancer 3(4):253–258. https://doi.org/10.1016/j.trecan.2017.02.005 [DOI: 10.1016/j.trecan.2017.02.005]
  11. Ballinger ML, Pattnaik S, Mundra PA, Zaheed M, Rath E, Priestley P, Baber J, Ray-Coquard I, Isambert N, Causeret S, van der Graaf WTA, Puri A, Duffaud F, Le Cesne A, Seddon B, Chandrasekar C, Schiffman JD, Brohl AS, James PA, Kurtz JE, Penel N, Myklebost O, Meza-Zepeda LA, Pickett H, Kansara M, Waddell N, Kondrashova O, Pearson JV, Barbour AP, Li S, Nguyen TL, Fatkin D, Graham RM, Giannoulatou E, Green MJ, Kaplan W, Ravishankar S, Copty J, Powell JE, Cuppen E, van Eijk K, Veldink J, Ahn JH, Kim JE, Randall RL, Tucker K, Judson I, Sarin R, Ludwig T, Genin E, Deleuze JF, French Exome Project Consortium, Haber M, Marshall G, Cairns MJ, Blay JY, International Sarcoma Kindred Study, Thomas DM, Tattersall M, Neuhaus S, Lewis C, Tucker K, Carey-Smith R, Wood D, Porceddu S, Dickinson I, Thorne H, James P, Ray-Coquard I, Blay JY, Cassier P, Le Cesne A, Duffaud F, Penel N, Isambert N, Kurtz JE, Puri A, Sarin R, Ahn JH, Kim JE, Ward I, Judson I, van der Graaf W, Seddon B, Chandrasekar C, Rickar R, Hennig I, Schiffman J, Randall RL, Silvestri A, Zaratzian A, Tayao M, Walwyn K, Niedermayr E, Mang D, Clark R, Thorpe T, MacDonald J, Riddell K, Mar J, Fennelly V, Wicht A, Zielony B, Galligan E, Glavich G, Stoeckert J, Williams L, Djandjgava L, Buettner I, Osinki C, Stephens S, Rogasik M, Bouclier L, Girodet M, Charreton A, Fayet Y, Crasto S, Sandupatla B, Yoon Y, Je N, Thompson L, Fowler T, Johnson B, Petrikova G, Hambridge T, Hutchins A, Bottero D, Scanlon D, Stokes-Denson J, Génin E, Campion D, Dartigues JF, Deleuze JF, Lambert JC, Redon R, Ludwig T, Grenier-Boley B, Letort S, Lindenbaum P, Meyer V, Quenez O, Dina C, Bellenguez C, Le Clézio CC, Giemza J, Chatel S, Férec C, Le Marec H, Letenneur L, Nicolas G, Rouault K (2023) Heritable defects in telomere and mitotic function selectively predispose to sarcomas. Science 379(6629):253–260. https://doi.org/10.1126/science.abj4784 [DOI: 10.1126/science.abj4784]
  12. Barragan R, Ortega-Azorin C, Sorli JV, Asensio EM, Coltell O, St-Onge MP, Portoles O, Corella D (2021) Effect of physical activity, smoking, and sleep on telomere length: a systematic review of observational and intervention studies. J Clin Med 11(1):76. https://doi.org/10.3390/jcm11010076 [DOI: 10.3390/jcm11010076]
  13. Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X, Amin SB, Akdemir KC, Seth S, Song X, Wang Q, Lichtenberg T, Hu J, Zhang J, Zheng S, Verhaak RG (2017) Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet 49(3):349–357. https://doi.org/10.1038/ng.3781 [DOI: 10.1038/ng.3781]
  14. Bodelon C, Savage SA, Gadalla SM (2014) Telomeres in molecular epidemiology studies. Prog Mol Biol Transl Sci 125:113–131. https://doi.org/10.1016/B978-0-12-397898-1.00005-0 [DOI: 10.1016/B978-0-12-397898-1.00005-0]
  15. Bonnell E, Pasquier E, Wellinger RJ (2021) Telomere replication: solving multiple end replication problems. Front Cell Dev Biol 9:668171. https://doi.org/10.3389/fcell.2021.668171 [DOI: 10.3389/fcell.2021.668171]
  16. Brown DW, Zhou W, Wang Y, Jones K, Luo W, Dagnall C, Teshome K, Klein A, Zhang T, Lin SH, Lee OW, Khan S, Vo JB, Hutchinson A, Liu J, Wang J, Zhu B, Hicks B, Martin AS, Spellman SR, Wang T, Deeg HJ, Gupta V, Lee SJ, Freedman ND, Yeager M, Chanock SJ, Savage SA, Saber W, Gadalla SM, Machiela MJ (2022) Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis. Nat Commun 13(1):5284. https://doi.org/10.1038/s41467-022-32986-7 [DOI: 10.1038/s41467-022-32986-7]
  17. Calvete O, Martinez P, Garcia-Pavia P, Benitez-Buelga C, Paumard-Hernandez B, Fernandez V, Dominguez F, Salas C, Romero-Laorden N, Garcia-Donas J, Carrillo J, Perona R, Trivino JC, Andres R, Cano JM, Rivera B, Alonso-Pulpon L, Setien F, Esteller M, Rodriguez-Perales S, Bougeard G, Frebourg T, Urioste M, Blasco MA, Benitez J (2015) A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families. Nat Commun 6:8383. https://doi.org/10.1038/ncomms9383 [DOI: 10.1038/ncomms9383]
  18. Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30(10):e47 [DOI: 10.1093/nar/30.10.e47]
  19. Chakravarti D, LaBella KA, DePinho RA (2021) Telomeres: history, health, and hallmarks of aging. Cell 184(2):306–322. https://doi.org/10.1016/j.cell.2020.12.028 [DOI: 10.1016/j.cell.2020.12.028]
  20. Chen B, Yan Y, Wang H, Xu J (2023) Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies. Aging Cell 22(7):e13874. https://doi.org/10.1111/acel.13874 [DOI: 10.1111/acel.13874]
  21. Claude E, Decottignies A (2020) Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof. Curr Opin Genet Dev 60:1–8. https://doi.org/10.1016/j.gde.2020.01.002 [DOI: 10.1016/j.gde.2020.01.002]
  22. Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ, Rafelt S, Moore J, Nelson C, Soranzo N, Zhai G, Valdes AM, Blackburn H, Mateo Leach I, de Boer RA, Kimura M, Aviv A, Wellcome Trust Case Control Consortium, Goodall AH, Ouwehand W, van Veldhuisen DJ, van Gilst WH, Navis G, Burton PR, Tobin MD, Hall AS, Thompson JR, Spector T, Samani NJ (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42(3):197–199. https://doi.org/10.1038/ng.532 [DOI: 10.1038/ng.532]
  23. Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, Mateo Leach I, Salo P, Hägg S, Matthews MK, Palmen J, Norata GD, O’Reilly PF, Saleheen D, Amin N, Balmforth AJ, Beekman M, de Boer RA, Böhringer S, Braund PS, Burton PR, de Craen AJ, Denniff M, Dong Y, Douroudis K, Dubinina E, Eriksson JG, Garlaschelli K, Guo D, Hartikainen AL, Henders AK, Houwing-Duistermaat JJ, Kananen L, Karssen LC, Kettunen J, Klopp N, Lagou V, van Leeuwen EM, Madden PA, Mägi R, Magnusson PK, Männistö S, McCarthy MI, Medland SE, Mihailov E, Montgomery GW, Oostra BA, Palotie A, Peters A, Pollard H, Pouta A, Prokopenko I, Ripatti S, Salomaa V, Suchiman HE, Valdes AM, Verweij N, Viñuela A, Wang X, Wichmann HE, Widen E, Willemsen G, Wright MJ, Xia K, Xiao X, van Veldhuisen DJ, Catapano AL, Tobin MD, Hall AS, Blakemore AI, van Gilst WH, Zhu H, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Talmud PJ, Pedersen NL, Perola M, Ouwehand W, Kaprio J, Martin NG, van Duijn CM, Hovatta I, Gieger C, Metspalu A, Boomsma DI, Jarvelin MR, Slagboom PE, Thompson JR, Spector TD, van der Harst P, Samani NJ (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45(4):422–427, 427e421–422. https://doi.org/10.1038/ng.2528 [DOI: 10.1038/ng.2528]
  24. Codd V, Wang Q, Allara E, Musicha C, Kaptoge S, Stoma S, Jiang T, Hamby SE, Braund PS, Bountziouka V, Budgeon CA, Denniff M, Swinfield C, Papakonstantinou M, Sheth S, Nanus DE, Warner SC, Wang M, Khera AV, Eales J, Ouwehand WH, Thompson JR, Di Angelantonio E, Wood AM, Butterworth AS, Danesh JN, Nelson CP, Samani NJ (2021) Polygenic basis and biomedical consequences of telomere length variation. Nat Genet 53(10):1425–1433. https://doi.org/10.1038/s41588-021-00944-6 [DOI: 10.1038/s41588-021-00944-6]
  25. Dagnall CL, Hicks B, Teshome K, Hutchinson AA, Gadalla SM, Khincha PP, Yeager M, Savage SA (2017) Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement. PLoS ONE 12(9):e0184098. https://doi.org/10.1371/journal.pone.0184098 [DOI: 10.1371/journal.pone.0184098]
  26. de Lange T (2018) Shelterin-mediated telomere protection. Annu Rev Genet 52:223–247. https://doi.org/10.1146/annurev-genet-032918-021921 [DOI: 10.1146/annurev-genet-032918-021921]
  27. De Rosa M, Johnson SA, Opresko PL (2021) Roles for the 8-oxoguanine DNA repair system in protecting telomeres from oxidative stress. Front Cell Dev Biol 9:758402. https://doi.org/10.3389/fcell.2021.758402 [DOI: 10.3389/fcell.2021.758402]
  28. DeBoy EA, Tassia MG, Schratz KE, Yan SM, Cosner ZL, McNally EJ, Gable DL, Xiang Z, Lombard DB, Antonarakis ES, Gocke CD, McCoy RC, Armanios M (2023) Familial clonal hematopoiesis in a long telomere syndrome. N Engl J Med 388(26):2422–2433. https://doi.org/10.1056/NEJMoa2300503 [DOI: 10.1056/NEJMoa2300503]
  29. Demanelis K, Jasmine F, Chen LS, Chernoff M, Tong L, Delgado D, Zhang C, Shinkle J, Sabarinathan M, Lin H, Ramirez E, Oliva M, Kim-Hellmuth S, Stranger BE, Lai TP, Aviv A, Ardlie KG, Aguet F, Ahsan H, GTEx Consortium, Doherty JA, Kibriya MG, Pierce BL (2020) Determinants of telomere length across human tissues. Science 369(6509):eaaz6876. https://doi.org/10.1126/science.aaz6876 [DOI: 10.1126/science.aaz6876]
  30. Gadalla SM, Khincha PP, Katki HA, Giri N, Wong JYY, Spellman S, Yanovski JA, Han JC, De Vivo I, Alter BP, Savage SA (2016) The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita. Mol Genet Genomic Med 4(4):475–479. https://doi.org/10.1002/mgg3.220 [DOI: 10.1002/mgg3.220]
  31. Gao J, Pickett HA (2022) Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Nat Rev Cancer 22(9):515–532. https://doi.org/10.1038/s41568-022-00490-1 [DOI: 10.1038/s41568-022-00490-1]
  32. Gardner M, Bann D, Wiley L, Cooper R, Hardy R, Nitsch D, Martin-Ruiz C, Shiels P, Sayer AA, Barbieri M, Bekaert S, Bischoff C, Brooks-Wilson A, Chen W, Cooper C, Christensen K, De Meyer T, Deary I, Der G, Diez Roux A, Fitzpatrick A, Hajat A, Halaschek-Wiener J, Harris S, Hunt SC, Jagger C, Jeon HS, Kaplan R, Kimura M, Lansdorp P, Li C, Maeda T, Mangino M, Nawrot TS, Nilsson P, Nordfjall K, Paolisso G, Ren F, Riabowol K, Robertson T, Roos G, Staessen JA, Spector T, Tang N, Unryn B, van der Harst P, Woo J, Xing C, Yadegarfar ME, Park JY, Young N, Kuh D, von Zglinicki T, Ben-Shlomo Y, Halcyon Study Team (2014) Gender and telomere length: systematic review and meta-analysis. Exp Gerontol 51:15–27. https://doi.org/10.1016/j.exger.2013.12.004 [DOI: 10.1016/j.exger.2013.12.004]
  33. Gong Y, Stock AJ, Liu Y (2020) The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants. Curr Opin Genet Dev 60:48–55. https://doi.org/10.1016/j.gde.2020.02.002 [DOI: 10.1016/j.gde.2020.02.002]
  34. Gutierrez-Rodrigues F, Santana-Lemos BA, Scheucher PS, Alves-Paiva RM, Calado RT (2014) Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans. PLoS ONE 9(11):e113747 [DOI: 10.1371/journal.pone.0113747]
  35. Hansen ME, Hunt SC, Stone RC, Horvath K, Herbig U, Ranciaro A, Hirbo J, Beggs W, Reiner AP, Wilson JG, Kimura M, De Vivo I, Chen MM, Kark JD, Levy D, Nyambo T, Tishkoff SA, Aviv A (2016) Shorter telomere length in Europeans than in Africans due to polygenetic adaptation. Hum Mol Genet 25(11):2324–2330. https://doi.org/10.1093/hmg/ddw070 [DOI: 10.1093/hmg/ddw070]
  36. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621 [DOI: 10.1016/0014-4827(61)90192-6]
  37. He H, Li W, Comiskey DF, Liyanarachchi S, Nieminen TT, Wang Y, DeLap KE, Brock P, de la Chapelle A (2020) A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres. Thyroid 30(2):204–213. https://doi.org/10.1089/thy.2019.0156 [DOI: 10.1089/thy.2019.0156]
  38. Hemann MT, Strong MA, Hao LY, Greider CW (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107(1):67–77. https://doi.org/10.1016/s0092-8674(01)00504-9 [DOI: 10.1016/s0092-8674(01)00504-9]
  39. Henry ML, Osborne J, Else T (1993) POT1 tumor predisposition. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (eds) GeneReviews((R)). University of Washington, Seattle, WA. https://www.ncbi.nlm.nih.gov/pubmed/33119245
  40. Herrera-Mullar J, Fulk K, Brannan T, Yussuf A, Polfus L, Richardson ME, Horton C (2023) Characterization of POT1 tumor predisposition syndrome: Tumor prevalence in a clinically diverse hereditary cancer cohort. Genet Med 25(11):100937. https://doi.org/10.1016/j.gim.2023.100937 [DOI: 10.1016/j.gim.2023.100937]
  41. Hunt SC, Chen W, Gardner JP, Kimura M, Srinivasan SR, Eckfeldt JH, Berenson GS, Aviv A (2008) Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell 7(4):451–458. https://doi.org/10.1111/j.1474-9726.2008.00397.x [DOI: 10.1111/j.1474-9726.2008.00397.x]
  42. Khincha PP, Dagnall CL, Hicks B, Jones K, Aviv A, Kimura M, Katki H, Aubert G, Giri N, Alter BP, Savage SA, Gadalla SM (2017) Correlation of leukocyte telomere length measurement methods in patients with dyskeratosis congenita and in their unaffected relatives. Int J Mol Sci 18(8):1765. https://doi.org/10.3390/ijms18081765 [DOI: 10.3390/ijms18081765]
  43. Knight SW, Heiss NS, Vulliamy TJ, Greschner S, Stavrides G, Pai GS, Lestringant G, Varma N, Mason PJ, Dokal I, Poustka A (1999) X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet 65(1):50–58. https://doi.org/10.1086/302446 [DOI: 10.1086/302446]
  44. Lai TP, Zhang N, Noh J, Mender I, Tedone E, Huang E, Wright WE, Danuser G, Shay JW (2017) A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat Commun 8(1):1356. https://doi.org/10.1038/s41467-017-01291-z [DOI: 10.1038/s41467-017-01291-z]
  45. Lai TP, Wright WE, Shay JW (2018) Comparison of telomere length measurement methods. Philos Trans R Soc Lond B Biol Sci 373(1741):20160451. https://doi.org/10.1098/rstb.2016.0451 [DOI: 10.1098/rstb.2016.0451]
  46. Lansdorp PM (2022a) Telomeres, aging, and cancer: the big picture. Blood 139(6):813–821. https://doi.org/10.1182/blood.2021014299 [DOI: 10.1182/blood.2021014299]
  47. Lansdorp PM (2022b) Telomeres, telomerase and cancer. Arch Med Res 53(8):741–746. https://doi.org/10.1016/j.arcmed.2022.10.004 [DOI: 10.1016/j.arcmed.2022.10.004]
  48. Lee M, Napier CE, Yang SF, Arthur JW, Reddel RR, Pickett HA (2017) Comparative analysis of whole genome sequencing-based telomere length measurement techniques. Methods 114:4–15. https://doi.org/10.1016/j.ymeth.2016.08.008 [DOI: 10.1016/j.ymeth.2016.08.008]
  49. Lin J, Epel E (2022) Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res Rev 73:101507. https://doi.org/10.1016/j.arr.2021.101507 [DOI: 10.1016/j.arr.2021.101507]
  50. Lin TT, Norris K, Heppel NH, Pratt G, Allan JM, Allsup DJ, Bailey J, Cawkwell L, Hills R, Grimstead JW, Jones RE, Britt-Compton B, Fegan C, Baird DM, Pepper C (2014) Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br J Haematol 167(2):214–223. https://doi.org/10.1111/bjh.13023 [DOI: 10.1111/bjh.13023]
  51. Lindrose AR, McLester-Davis LWY, Tristano RI, Kataria L, Gadalla SM, Eisenberg DTA, Verhulst S, Drury S (2021) Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature. PLoS ONE 16(1):e0245582. https://doi.org/10.1371/journal.pone.0245582 [DOI: 10.1371/journal.pone.0245582]
  52. Machiela MJ, Hofmann JN, Carreras-Torres R, Brown KM, Johansson M, Wang Z, Foll M, Li P, Rothman N, Savage SA, Gaborieau V, McKay JD, Ye Y, Henrion M, Bruinsma F, Jordan S, Severi G, Hveem K, Vatten LJ, Fletcher T, Koppova K, Larsson SC, Wolk A, Banks RE, Selby PJ, Easton DF, Pharoah P, Andreotti G, Freeman LEB, Koutros S, Albanes D, Mannisto S, Weinstein S, Clark PE, Edwards TE, Lipworth L, Gapstur SM, Stevens VL, Carol H, Freedman ML, Pomerantz MM, Cho E, Kraft P, Preston MA, Wilson KM, Gaziano JM, Sesso HS, Black A, Freedman ND, Huang WY, Anema JG, Kahnoski RJ, Lane BR, Noyes SL, Petillo D, Colli LM, Sampson JN, Besse C, Blanche H, Boland A, Burdette L, Prokhortchouk E, Skryabin KG, Yeager M, Mijuskovic M, Ognjanovic M, Foretova L, Holcatova I, Janout V, Mates D, Mukeriya A, Rascu S, Zaridze D, Bencko V, Cybulski C, Fabianova E, Jinga V, Lissowska J, Lubinski J, Navratilova M, Rudnai P, Szeszenia-Dabrowska N, Benhamou S, Cancel-Tassin G, Cussenot O, Bueno-de-Mesquita HB, Canzian F, Duell EJ, Ljungberg B, Sitaram RT, Peters U, White E, Anderson GL, Johnson L, Luo J, Buring J, Lee IM, Chow WH, Moore LE, Wood C, Eisen T, Larkin J, Choueiri TK, Lathrop GM, Teh BT, Deleuze JF, Wu X, Houlston RS, Brennan P, Chanock SJ, Scelo G, Purdue MP (2017) Genetic variants related to longer telomere length are associated with increased risk of renal cell carcinoma. Eur Urol 72(5):747–754. https://doi.org/10.1016/j.eururo.2017.07.015 [DOI: 10.1016/j.eururo.2017.07.015]
  53. Mangino M, Christiansen L, Stone R, Hunt SC, Horvath K, Eisenberg DT, Kimura M, Petersen I, Kark JD, Herbig U, Reiner AP, Benetos A, Codd V, Nyholt DR, Sinnreich R, Christensen K, Nassar H, Hwang SJ, Levy D, Bataille V, Fitzpatrick AL, Chen W, Berenson GS, Samani NJ, Martin NG, Tishkoff S, Schork NJ, Kyvik KO, Dalgård C, Spector TD, Aviv A (2015) DCAF4, a novel gene associated with leucocyte telomere length. J Med Genet 52(3):157–162. https://doi.org/10.1136/jmedgenet-2014-102681 [DOI: 10.1136/jmedgenet-2014-102681]
  54. McClintock B (1939) The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc Natl Acad Sci USA 25(8):405–416. https://doi.org/10.1073/pnas.25.8.405 [DOI: 10.1073/pnas.25.8.405]
  55. McMaster ML, Sun C, Landi MT, Savage SA, Rotunno M, Yang XR, Jones K, Vogt A, Hutchinson A, Zhu B, Wang M, Hicks B, Thirunavukarason A, Stewart DR, Koutros S, Goldstein AM, Chanock SJ, Caporaso NE, Tucker MA, Goldin LR, Liu Y (2018) Germline mutations in protection of telomeres 1 in two families with Hodgkin lymphoma. Br J Haematol 181(3):372–377. https://doi.org/10.1111/bjh.15203 [DOI: 10.1111/bjh.15203]
  56. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402(6761):551–555. https://doi.org/10.1038/990141 [DOI: 10.1038/990141]
  57. Moller P, Wils RS, Jensen DM, Andersen MHG, Roursgaard M (2018) Telomere dynamics and cellular senescence: an emerging field in environmental and occupational toxicology. Crit Rev Toxicol 48(9):761–788. https://doi.org/10.1080/10408444.2018.1538201 [DOI: 10.1080/10408444.2018.1538201]
  58. Muller HJ (1940) An analysis of the process of structural change in chromosomes of Drosophila. J Genet 40:1–66. https://doi.org/10.1007/BF02982481 [DOI: 10.1007/BF02982481]
  59. Nassour J, Schmidt TT, Karlseder J (2021) Telomeres and cancer: resolving the paradox. Annu Rev Cancer Biol 5(1):59–77. https://doi.org/10.1146/annurev-cancerbio-050420-023410 [DOI: 10.1146/annurev-cancerbio-050420-023410]
  60. Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, Savage SA (2022) Disease progression and clinical outcomes in telomere biology disorders. Blood 139(12):1807–1819. https://doi.org/10.1182/blood.2021013523 [DOI: 10.1182/blood.2021013523]
  61. Norris K, Walne AJ, Ponsford MJ, Cleal K, Grimstead JW, Ellison A, Alnajar J, Dokal I, Vulliamy T, Baird DM (2021) High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders. Hum Genet 140(6):945–955. https://doi.org/10.1007/s00439-021-02257-4 [DOI: 10.1007/s00439-021-02257-4]
  62. Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41(1):181–190. https://doi.org/10.1016/0022-5193(73)90198-7 [DOI: 10.1016/0022-5193(73)90198-7]
  63. Polygenic Risk Score Task Force of the International Common Disease Alliance (2021) Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nat Med 27(11):1876–1884. https://doi.org/10.1038/s41591-021-01549-6 [DOI: 10.1038/s41591-021-01549-6]
  64. Prescott J, Kraft P, Chasman D, Savage S, Mirabello L, Berndt S, Weissfeld J, Han J, Hayes R, Chanock S, Hunter D, De Vivo I (2011) GWAS of telomere length. http://www.gwascentral.org/study/HGVST833
  65. Prescott J, Wentzensen IM, Savage SA, De Vivo I (2012) Epidemiologic evidence for a role of telomere dysfunction in cancer etiology. Mutat Res 730(1–2):75–84. https://doi.org/10.1016/j.mrfmmm.2011.06.009 [DOI: 10.1016/j.mrfmmm.2011.06.009]
  66. Raj HA, Lai TP, Niewisch MR, Giri N, Wang Y, Spellman SR, Aviv A, Gadalla SM, Savage SA (2023) The distribution and accumulation of the shortest telomeres in telomere biology disorders. Br J Haematol 203(5):820–828. https://doi.org/10.1111/bjh.18945 [DOI: 10.1111/bjh.18945]
  67. Revy P, Kannengiesser C, Bertuch AA (2023) Genetics of human telomere biology disorders. Nat Rev Genet 24(2):86–108. https://doi.org/10.1038/s41576-022-00527-z [DOI: 10.1038/s41576-022-00527-z]
  68. Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, López-Otín C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA, Adams DJ (2014) POT1 loss-of-function variants predispose to familial melanoma. Nat Genet 46(5):478–481. https://doi.org/10.1038/ng.2947 [DOI: 10.1038/ng.2947]
  69. Rossiello F, Jurk D, Passos JF, d’Adda di Fagagna F (2022) Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol 24(2):135–147. https://doi.org/10.1038/s41556-022-00842-x [DOI: 10.1038/s41556-022-00842-x]
  70. Savage SA (2018) Beginning at the ends: telomeres and human disease. F1000Res 7:F1000 Faculty Rev-524. https://doi.org/10.12688/f1000research.14068.1 [DOI: 10.12688/f1000research.14068.1]
  71. Savage SA (2022) Dyskeratosis congenita and telomere biology disorders. Hematology Am Soc Hematol Educ Program 2022(1):637–648. https://doi.org/10.1182/hematology.2022000394 [DOI: 10.1182/hematology.2022000394]
  72. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP (2008) TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 82(2):501–509. https://doi.org/10.1016/j.ajhg.2007.10.004 [DOI: 10.1016/j.ajhg.2007.10.004]
  73. Saxena R, Bjonnes A, Prescott J, Dib P, Natt P, Lane J, Lerner M, Cooper JA, Ye Y, Li KW, Maubaret CG, Codd V, Brackett D, Mirabello L, Kraft P, Dinney CP, Stowell D, Peyton M, Ralhan S, Wander GS, Mehra NK, Salpea KD, Gu J, Wu X, Mangino M, Hunter DJ, De Vivo I, Humphries SE, Samani NJ, Spector TD, Savage SA, Sanghera DK (2014) Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort. Circ Cardiovasc Genet 7(3):287–295. https://doi.org/10.1161/CIRCGENETICS.113.000412 [DOI: 10.1161/CIRCGENETICS.113.000412]
  74. Schratz KE, Flasch DA, Atik CC, Cosner ZL, Blackford AL, Yang W, Gable DL, Vellanki PJ, Xiang Z, Gaysinskaya V, Vonderheide RH, Rooper LM, Zhang J, Armanios M (2023) T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell 41(4):807-817.e806. https://doi.org/10.1016/j.ccell.2023.03.005 [DOI: 10.1016/j.ccell.2023.03.005]
  75. Seow WJ, Cawthon RM, Purdue MP, Hu W, Gao YT, Huang WY, Weinstein SJ, Ji BT, Virtamo J, Hosgood HD 3rd, Bassig BA, Shu XO, Cai Q, Xiang YB, Min S, Chow WH, Berndt SI, Kim C, Lim U, Albanes D, Caporaso NE, Chanock S, Zheng W, Rothman N, Lan Q (2014) Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts. Cancer Res 74(15):4090–4098. https://doi.org/10.1158/0008-5472.CAN-14-0459 [DOI: 10.1158/0008-5472.CAN-14-0459]
  76. Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33(5):787–791. https://doi.org/10.1016/S0959-8049(97)00062-2 [DOI: 10.1016/S0959-8049(97)00062-2]
  77. Shay JW, Wright WE (2019) Telomeres and telomerase: three decades of progress. Nat Rev Genet 20(5):299–309. https://doi.org/10.1038/s41576-019-0099-1 [DOI: 10.1038/s41576-019-0099-1]
  78. Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, Ghiorzo P, Paillerets BB-D, Nagore E, Avri MF, Caporaso NE, McMaster ML, Cullen M, Wang Z, Zhang X, NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, French Familial Melanoma Study Group, Bruno W, Pastorino L, Queirolo P, Banuls-Roca J, Garcia-Casado Z, Vaysse A, Mohamdi H, Riazalhosseini Y, Foglio M, Jouenne F, Hua X, Hyland PL, Yin J, Vallabhaneni H, Chai W, Minghetti P, Pellegrini C, Ravichandran S, Eggermont A, Lathrop M, Peris K, Scarra GB, Landi G, Savage SA, Sampson JN, He J, Yeager M, Goldin LR, Demenais F, Chanock SJ, Tucker MA, Goldstein AM, Liu Y, Landi MT (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46(5):482–486. https://doi.org/10.1038/ng.2941 [DOI: 10.1038/ng.2941]
  79. Speedy HE, Kinnersley B, Chubb D, Broderick P, Law PJ, Litchfield K, Jayne S, Dyer MJS, Dearden C, Follows GA, Catovsky D, Houlston RS (2016) Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. Blood 128(19):2319–2326. https://doi.org/10.1182/blood-2016-01-695692 [DOI: 10.1182/blood-2016-01-695692]
  80. Sun C, Wang K, Stock AJ, Gong Y, Demarest TG, Yang B, Giri N, Harrington L, Alter BP, Savage SA, Bohr VA, Liu Y (2020) Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction. EMBO J 39(21):e103420. https://doi.org/10.15252/embj.2019103420 [DOI: 10.15252/embj.2019103420]
  81. Team Telomere (2022) Telomere biology disorders diagnosis and management guidelines (Agarwal S, Savage SA, Stevens K, Raj H, Carson HK, eds). Team Telomere, Inc. https://teamtelomere.org/diagnosis-management-guidelines/
  82. Telomeres Mendelian Randomization Collaboration, Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN, Bowden J, Wade KH, Timpson NJ, Evans DM, Willeit P, Aviv A, Gaunt TR, Hemani G, Mangino M, Ellis HP, Kurian KM, Pooley KA, Eeles RA, Lee JE, Fang S, Chen WV, Law MH, Bowdler LM, Iles MM, Yang Q, Worrall BB, Markus HS, Hung RJ, Amos CI, Spurdle AB, Thompson DJ, O’Mara TA, Wolpin B, Amundadottir L, Stolzenberg-Solomon R, Trichopoulou A, Onland-Moret NC, Lund E, Duell EJ, Canzian F, Severi G, Overvad K, Gunter MJ, Tumino R, Svenson U, van Rij A, Baas AF, Bown MJ, Samani NJ, van t’Hof FNG, Tromp G, Jones GT, Kuivaniemi H, Elmore JR, Johansson M, Mckay J, Scelo G, Carreras-Torres R, Gaborieau V, Brennan P, Bracci PM, Neale RE, Olson SH, Gallinger S, Li D, Petersen GM, Risch HA, Klein AP, Han J, Abnet CC, Freedman ND, Taylor PR, Maris JM, Aben KK, Kiemeney LA, Vermeulen SH, Wiencke JK, Walsh KM, Wrensch M, Rice T, Turnbull C, Litchfield K, Paternoster L, Standl M, Abecasis GR, SanGiovanni JP, Li Y, Mijatovic V, Sapkota Y, Low SK, Zondervan KT, Montgomery GW, Nyholt DR, van Heel DA, Hunt K, Arking DE, Ashar FN, Sotoodehnia N, Woo D, Rosand J, Comeau ME, Brown WM, Silverman EK, Hokanson JE, Cho MH, Hui J, Ferreira MA, Thompson PJ, Morrison AC, Felix JF, Smith NL, Christiano AM, Petukhova L, Betz RC, Fan X, Zhang X, Zhu C, Langefeld CD, Thompson SD, Wang F, Lin X, Schwartz DA, Fingerlin T, Rotter JI, Cotch MF, Jensen RA, Munz M, Dommisch H, Schaefer AS, Han F, Ollila HM, Hillary RP, Albagha O, Ralston SH, Zeng C, Zheng W, Shu XO, Reis A, Uebe S, Hüffmeier U, Kawamura Y, Otowa T, Sasaki T, Hibberd ML, Davila S, Xie G, Siminovitch K, Bei JX, Zeng YX, Försti A, Chen B, Landi S, Franke A, Fischer A, Ellinghaus D, Flores C, Noth I, Ma SF, Foo JN, Liu J, Kim JW, Cox DG, Delattre O, Mirabeau O, Skibola CF, Tang CS, Garcia-Barcelo M, Chang KP, Su WH, Chang YS, Martin NG, Gordon S, Wade TD, Lee C, Kubo M, Cha PC, Nakamura Y, Levy D, Kimura M, Hwang SJ, Hunt S, Spector T, Soranzo N, Manichaikul AW, Barr RG, Kahali B, Speliotes E, Yerges-Armstrong LM, Cheng CY, Jonas JB, Wong TY, Fogh I, Lin K, Powell JF, Rice K, Relton CL, Martin RM, Davey Smith G (2017) Association between telomere length and risk of cancer and non-neoplastic diseases: a Mendelian randomization study. JAMA Oncol 3(5):636–651. https://doi.org/10.1001/jamaoncol.2016.5945 [DOI: 10.1001/jamaoncol.2016.5945]
  83. Tham CY, Poon L, Yan T, Koh JYP, Ramlee MK, Teoh VSI, Zhang S, Cai Y, Hong Z, Lee GS, Liu J, Song HW, Hwang WYK, Teh BT, Tan P, Xu L, Koh AS, Osato M, Li S (2023) High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform. Nat Commun 14(1):281. https://doi.org/10.1038/s41467-023-35823-7 [DOI: 10.1038/s41467-023-35823-7]
  84. Trigueros-Motos L (2014) Mutations in POT1 predispose to familial cutaneous malignant melanoma. Clin Genet 86(3):217–218. https://doi.org/10.1111/cge.12416 [DOI: 10.1111/cge.12416]
  85. Tummala H, Walne A, Dokal I (2022) The biology and management of dyskeratosis congenita and related disorders of telomeres. Expert Rev Hematol 15(8):685–696. https://doi.org/10.1080/17474086.2022.2108784 [DOI: 10.1080/17474086.2022.2108784]
  86. Wand H, Kalia SS, Helm BM, Suckiel SA, Brockman D, Vriesen N, Goudar RK, Austin J, Yanes T (2023) Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: a practice resource from the National Society of Genetic Counselors. J Genet Couns 32(3):558–575. https://doi.org/10.1002/jgc4.1668 [DOI: 10.1002/jgc4.1668]
  87. Wentzensen IM, Mirabello L, Pfeiffer RM, Savage SA (2011) The association of telomere length and cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 20(6):1238–1250. https://doi.org/10.1158/1055-9965.EPI-11-0005 [DOI: 10.1158/1055-9965.EPI-11-0005]
  88. Yabroff KR, Mariotto A, Tangka F, Zhao J, Islami F, Sung H, Sherman RL, Henley SJ, Jemal A, Ward EM (2021) Annual report to the Nation on the Status of Cancer, part 2: patient economic burden associated with cancer care. J Natl Cancer Inst 113(12):1670–1682. https://doi.org/10.1093/jnci/djab192 [DOI: 10.1093/jnci/djab192]
  89. Ye Q, Apsley AT, Etzel L, Hastings WJ, Kozlosky JT, Walker C, Wolf SE, Shalev I (2023) Telomere length and chronological age across the human lifespan: a systematic review and meta-analysis of 414 study samples including 743,019 individuals. Ageing Res Rev 90:102031. https://doi.org/10.1016/j.arr.2023.102031 [DOI: 10.1016/j.arr.2023.102031]
  90. Zade NH, Khattar E (2023) POT1 mutations cause differential effects on telomere length leading to opposing disease phenotypes. J Cell Physiol 238(6):1237–1255. https://doi.org/10.1002/jcp.31034 [DOI: 10.1002/jcp.31034]

MeSH Term

Humans
Reproducibility of Results
Telomere
Telomere Shortening
Cellular Senescence
Genomic Instability
Telomerase
Neoplasms

Chemicals

Telomerase
Journal Article Review
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0telomerescancertelomereTLvariantslengthgermlineshortassociatedrisksTelomererarecommonagemaintenancegenesbiologyelevatedleukemiacellcarcinomascoreriskPolygenicTelomeresnucleoproteincomplexchromosomeendsessentialgenomicstabilityBaselinedeterminedgeneticshortenssusceptiblecertainenvironmentalexposuresCellularsenescenceapoptosisnormallytriggeredreachcriticallycellsovercomeprotectivemechanismscontinuedividedespitechromosomalinstabilityRarecauseexceedingly< 1stpercentiledisordersbonemarrowfailuremyelodysplasticsyndromeacutemyeloidsquamoushead/neckanogenitalregionsLongduedifferentcancerschroniclymphocyticsarcomaEarlyepidemiologystudiesgeneralpopulationlackedreproducibilitynewmethodsincludingcreationpolygenicusingfoundlongerexcessrenalgliomalungothersbecomeclearcomesetiologylong"justright"importantminimizingrisk:findingGoldilocksCancerDyskeratosiscongenitaGeneticvariantinheritancedisorder

Similar Articles

Cited By (12)