J Korean Med Sci.  2012 Feb;27(2):141-145. 10.3346/jkms.2012.27.2.141.

Telomerase Activity and the Risk of Lung Cancer

• Jeon HS
• Choi JE
• Jung DK
• Choi YY
• Kang HG
• Lee WK
• Yoo SS
• Lim JO
• Park JY

• KMID: 1120150
• DOI: http://doi.org/10.3346/jkms.2012.27.2.141

Abstract

Telomerase play a key role in the maintenance of telomere length and chromosome integrity. We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Telomerase activity in peripheral blood mononuclear cells was measured by a PCR-designed telomeric repeat amplification protocol in 63 lung cancer patients and 190 healthy controls that were matched for age, gender, and smoking status. Telomerase activity was significantly lower in the lung cancer patients than in controls (mean +/- standard deviation; 1.32 +/- 1.65 vs 2.60 +/- 3.09, P < 1 x 10(-4)). When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (Ptrend = 1 x 10(-4)). Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a significantly increased risk of lung cancer compared to subjects with high telomerase activity (adjusted odds ratio = 3.05, 95% confidence interval = 1.60-5.82, P = 7 x 10-4). These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer.

Keyword

Lung Cancer; Telomerase Activity; Susceptibility

MeSH Terms

Age Factors
Aged
Case-Control Studies
Female
Humans
Leukocytes, Mononuclear/enzymology/immunology
Lung Neoplasms/*enzymology/*etiology
Male
Middle Aged
Odds Ratio
Risk Factors
Sex Factors
Smoking
Telomerase/*blood

Reference

1. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Gene Dev. 2005. 19:2100–2110.

2. Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999. 97:527–538.

3. Blasco MA. Telomeres and human disease: aging, cancer and beyond. Nat Rev Genet. 2005. 6:611–622.

4. Calado RT, Young NS. Telomere disease. N Engl J Med. 2009. 361:2353–2365.

5. Eisenberg DT. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol. 2011. 23:149–167.

6. Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989. 59:521–529.

7. Shay JW, Zou Y, Hiyama E, Wright WE. Telomerase and cancer. Hum Mol Genet. 2001. 10:677–685.

8. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Hum Genet. 1998. 102:397–402.

9. Bischoff C, Graakjaer J, Petersen HC, Hjelmborg JV, Vaupel JW, Bohr V, Koelvraa S, Christensen K. The heritability of telomere length among the elderly and oldest-old. Twin Res Hum Genet. 2005. 8:433–439.

10. Andrew T, Aviv A, Falchi M, Surdulescu GL, Gardner JP, Lu X, Kimura M, Kato BS, Valdes AM, Spector TD. Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J Hum Genet. 2006. 78:480–486.

11. Mangino M, Richards JB, Soranzo N, Zhai G, Aviv A, Valdes AM, Samani NJ, Deloukas P, Spector TD. A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. J Med Genet. 2009. 46:451–454.

12. 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, Goodall AH, Ouwehand W, van Veldhuisen DJ, van Gilst WH, Navis G, Burton PR, Tobin MD, Hall AS, Thompson JR, Spector T, Samani NJ. Wellcome Trust Case Control Consortium. Common variants near TERC are associated with mean telomere length. Nat Genet. 2010. 42:197–199.

13. Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, Chen W, Bis JC, Fitzpatrick AL, Smith E, Johnson AD, Gardner JP, Srinivasan SR, Schork N, Rotter JI, Herbig U, Psaty BM, Sastrasinh M, Murray SS, Vasan RS, Province MA, Glazer NL, Lu X, Cao X, Kronmal R, Mangino M, Soranzo N, Spector TD, Berenson GS, Aviv A. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A. 2010. 107:9293–9298.

14. Jang JS, Choi YY, Lee WK, Choi JE, Cha SI, Kim YJ, Kim CH, Kam S, Jung TH, Park JY. Telomere length and the risk of lung cancer. Cancer Sci. 2008. 99:1385–1389.

15. Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstatter A, Kronenberg F, Kiechl S. Telomere length and risk of incident cancer and cancer mortality. JAMA. 2010. 304:69–75.

16. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994. 266:2011–2015.

17. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer. 1997. 33:787–791.

18. Wright WE, Shay JW. The two-stage mechanism controlling cellular senescence and immortalization. Exp Gerontol. 1992. 27:383–389.

19. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001. 11:S27–S31.

20. Blasco MA, Lee HW, Hande MP, Samper E, Landsdorp PM, DePinho RA, Greider CW. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997. 91:25–34.

21. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999. 96:701–712.

22. Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet. 2001. 28:155–159.

23. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000. 406:641–645.

24. Wu X, Amos CI, Zhu Y, Zhao H, Grossman BH, Shay JW, Luo S, Hong WK, Spitz MR. Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer Inst. 2003. 95:1211–1218.

25. McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan HE, Skorpen F, Elvestad MB, Vatten L, Njølstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis MM, Lubiñski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, González CA, Ramón Quirós J, Martínez C, Navarro C, Ardanaz E, Larrañaga N, Kham KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjønneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P. EPIC Study. Lung cancer susceptibility locus at 5p15.33. Nat Genet. 2008. 40:1404–1406.

26. Hsu CP, Hsu NY, Lee LW, Ko JL. Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter: effect on telomerase expression and telomere maintenance in non-small cell lung cancer. Eur J Cancer. 2006. 42:1466–1474.

27. Matsubara Y, Murata M, Yoshida T, Watanabe K, Saito I, Miyaki K, Omae K, Ikeda Y. Telomere length of normal leukocytes is affected by a functional polymorphism of hTERT. Biochem Biophys Res Commun. 2006. 341:128–131.

28. Choi JE, Kang HG, Jang JS, Choi YY, Kim MJ, Kim JS, Jeon HS, Lee WK, Cha SI, Kim CH, Kam S, Jung TH, Park JY. Polymorphisms in telomere maintenance genes and risk of lung cancer. Cancer Epidemiol Biomarkers Prev. 2009. 18:2773–2781.