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PMID: 28718437 Published · ppublish English Journal Article Review Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Mutations, Cancer and the Telomere Length Paradox.

Trends in cancer ·Vol. 3 ·No. 4 ·2017-00-00 ·Pages 253-258

Aviv A, Anderson JJ, Shay JW

Abstract

Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability - a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

Keywords
cancer clones evolution mutation stem cells telomeres
MeSH Terms
Humans Mutation Neoplasms/genetics Telomere/genetics
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Aviv Abraham
The Center of Human Development and Aging, New Jersey Medical School, Rutgers, Newark, NJ 07103, USA. Electronic address: [email protected].
Anderson James J
Center for Statistics and the Social Sciences and Center for Studies in Demography and Ecology, University of Washington, Seattle, WA 98105, USA.
Shay Jerry W
Department of Cell Biology, UT Southwestern Medical Center, Dallas TX, 75390, USA; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
References (45)
45 references, click to expand
  1. The p53 tumor suppressor participates in multiple cell cycle checkpoints.
    J Cell Physiol. 2006 Oct;209(1):13-20 PMID: 16741928
  2. Response to: Reliability and validity of telomere length measurements.
    Int J Epidemiol. 2016 Aug;45(4):1298-1301 PMID: 27880696
  3. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer.
    Br J Cancer. 1957 Jun;11(2):161-9 PMID: 13460138
  4. Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis.
    Circ Cardiovasc Genet. 2015 Feb;8(1):82-90 PMID: 25406241
  5. When one mutation is all it takes.
    Cancer Cell. 2015 Apr 13;27(4):433-4 PMID: 25873168
  6. Correction: TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants.
    Elife. 2016 Dec 20;5: PMID: 27997337
  7. The effect on melanoma risk of genes previously associated with telomere length.
    J Natl Cancer Inst. 2014 Sep 17;106(10):null PMID: 25231748
  8. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.
    Science. 2015 Jan 2;347(6217):78-81 PMID: 25554788
  9. The heritability of leucocyte telomere length dynamics.
    J Med Genet. 2015 May;52(5):297-302 PMID: 25770094
  10. Peto's paradox and the promise of comparative oncology.
    Philos Trans R Soc Lond B Biol Sci. 2015 Jul 19;370(1673):null PMID: 26056361
  11. A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study.
    Int J Cancer. 2013 Dec 1;133(11):2672-80 PMID: 23674344
  12. Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts.
    Cancer Res. 2014 Aug 1;74(15):4090-8 PMID: 24853549
  13. The Genetic Evolution of Melanoma from Precursor Lesions.
    N Engl J Med. 2015 Nov 12;373(20):1926-36 PMID: 26559571
  14. Shelterin: the protein complex that shapes and safeguards human telomeres.
    Genes Dev. 2005 Sep 15;19(18):2100-10 PMID: 16166375
  15. The telomere syndromes.
    Nat Rev Genet. 2012 Oct;13(10):693-704 PMID: 22965356
  16. Shorter telomere length in Europeans than in Africans due to polygenetic adaptation.
    Hum Mol Genet. 2016 Jun 1;25(11):2324-2330 PMID: 26936823
  17. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  18. Substantial contribution of extrinsic risk factors to cancer development.
    Nature. 2016 Jan 7;529(7584):43-7 PMID: 26675728
  19. Telomere length influences cancer cell differentiation in vivo.
    Mol Cell Biol. 2013 Aug;33(15):2988-95 PMID: 23716593
  20. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis.
    BMJ. 2014 Jul 08;349:g4227 PMID: 25006006
  21. Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect.
    Eur J Hum Genet. 2013 Oct;21(10):1163-8 PMID: 23321625
  22. Cancer-associated TERT promoter mutations abrogate telomerase silencing.
    Elife. 2015 Jul 21;4:null PMID: 26194807
  23. The long and short of telomeres and cancer association studies.
    J Natl Cancer Inst. 2013 Apr 3;105(7):448-9 PMID: 23468461
  24. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.
    Int J Cancer. 2015 Jul 15;137(2):311-9 PMID: 25516442
  25. Telomere Length and the Cancer-Atherosclerosis Trade-Off.
    PLoS Genet. 2016 Jul 07;12 (7):e1006144 PMID: 27386863
  26. Alteration of telomeric repeat length in adult and childhood solid neoplasias.
    Int J Oncol. 1995 Jan;6(1):13-6 PMID: 21556494
  27. Insights into the evolution of longevity from the bowhead whale genome.
    Cell Rep. 2015 Jan 6;10(1):112-22 PMID: 25565328
  28. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.
    Hum Mol Genet. 2016 Apr 15;25(8):1663-76 PMID: 27008888
  29. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
    JAMA. 2015 Nov 3;314(17):1850-60 PMID: 26447779
  30. Telomerase activity coevolves with body mass not lifespan.
    Aging Cell. 2007 Feb;6(1):45-52 PMID: 17173545
  31. Genetic determination of telomere size in humans: a twin study of three age groups.
    Am J Hum Genet. 1994 Nov;55(5):876-82 PMID: 7977349
  32. DCAF4, a novel gene associated with leucocyte telomere length.
    J Med Genet. 2015 Mar;52(3):157-62 PMID: 25624462
  33. Identification of seven loci affecting mean telomere length and their association with disease.
    Nat Genet. 2013 Apr;45(4):422-7, 427e1-2 PMID: 23535734
  34. The evolution of lifespan and age-dependent cancer risk.
    Trends Cancer. 2016 Oct;2(10 ):552-560 PMID: 28439564
  35. Role of telomeres and telomerase in cancer.
    Semin Cancer Biol. 2011 Dec;21(6):349-53 PMID: 22015685
  36. Commentary: The reliability of telomere length measurements.
    Int J Epidemiol. 2015 Oct;44(5):1683-6 PMID: 26403812
  37. Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer.
    Br J Cancer. 2015 Feb 17;112(4):769-76 PMID: 25562437
  38. Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease.
    Pediatrics. 2016 Apr;137(4): PMID: 26969272
  39. Does everyone develop covert cancer?
    Nat Rev Cancer. 2014 Apr;14(4):209-10 PMID: 25688403
  40. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination.
    Aging Cell. 2011 Oct;10(5):761-8 PMID: 21518243
  41. Telomere length, telomere-related genes, and breast cancer risk: the breast cancer health disparities study.
    Genes Chromosomes Cancer. 2013 Jul;52(7):595-609 PMID: 23629941
  42. The clonal evolution of tumor cell populations.
    Science. 1976 Oct 1;194(4260):23-8 PMID: 959840
  43. Connecting chromosomes, crisis, and cancer.
    Science. 2002 Jul 26;297(5581):565-9 PMID: 12142527
  44. Alternative splicing regulation of telomerase: a new paradigm?
    Trends Genet. 2014 Oct;30(10):430-8 PMID: 25172021
  45. Darwinian medicine: a case for cancer.
    Nat Rev Cancer. 2007 Mar;7(3):213-21 PMID: 17301845
Article Info
Journal
Trends in cancer
Abbr.
Trends Cancer
ISSN
2405-8025
DOI
10.1016/j.trecan.2017.02.005
Email
[email protected]
Published
2017-00-00
Epub
2017-00-27
Pages
253-258
Language
English
Region
United States
NLM ID
101665956
PMCID
PMC5903276
Subset
IM
Grants
NIA NIH HHS · R01 AG030678 · United States
NIA NIH HHS · R01 AG020132 · United States
NCRR NIH HHS · C06 RR030414 · United States
NCI NIH HHS · P50 CA070907 · United States
NHLBI NIH HHS · R01 HL134840 · United States
NIA NIH HHS · R01 AG021593 · United States
NIA NIH HHS · R21 AG046760 · United States
NHLBI NIH HHS · R01 HL116446 · United States
NHLBI NIH HHS · HHSN268201300007C · United States
NICHD NIH HHS · R01 HD071180 · United States
NCI NIH HHS · P30 CA142543 · United States
External Links
PubMed source DOI: 10.1016/j.trecan.2017.02.005 PMC Full Text View journal details
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