Abstract
Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes (TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT-CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case–control study of Caucasians nested within the Nurses’ Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT-CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) [95% confidence interval (95% CI)] of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14–1.81), 1.50 (1.14–1.98), 1.87 (1.19–2.91), and 0.73 (0.59–0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length (P for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility.
Similar content being viewed by others
Abbreviations
- SCC:
-
Squamous cell carcinoma
- BCC:
-
Basal cell carcinoma
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- UV:
-
Ultraviolet
References
Bataille V, Kato BS, Falchi M, Gardner J, Kimura M, Lens M, Perks U, Valdes AM, Bennett DC, Aviv A, Spector TD (2007) Nevus size and number are associated with telomere length and represent potential markers of a decreased senescence in vivo. Cancer Epidemiol Biomarkers Prev 16:1499–1502
Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:1171–1175
Blasco MA (2003) Mammalian telomeres and telomerase: why they matter for cancer and aging. Eur J Cell Biol 82:441–446
Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352
Broccoli D, Smogorzewska A, Chong L, de Lange T (1997) Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet 17:231–235
Campisi J, Kim SH, Lim CS, Rubio M (2001) Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol 36:1619–1637
Chang E, Harley CB (1995) Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 92:11190–11194
Chong L, van Steensel B, Broccoli D, Erdjument-Bromage H, Hanish J, Tempst P, de Lange T (1995) A human telomeric protein. Science 270:1663–1667
Gilchrest BA, Eller MS, Geller AC, Yaar M (1999) The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 340:1341–1348
Greider CW (1999) Telomeres do D-loop-T-loop. Cell 97:419–422
Haiman CA, Stram DO (2008) Utilizing HapMap and tagging SNPs. Methods Mol Med 141:37–54
Han J, Colditz GA, Hunter DJ (2006) Risk factors for skin cancers: a nested case-control study within the Nurses’ Health Study. Int J Epidemiol 35:1514–1521
Han J, Qureshi AA, Prescott J, Guo Q, Ye L, Hunter DJ, De Vivo I (2009) A prospective study of telomere length and the risk of skin cancer. J Invest Dermatol 129:415–421
Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T (1999) p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283:1321–1325
Kruk PA, Rampino NJ, Bohr VA (1995) DNA damage and repair in telomeres: relation to aging. Proc Natl Acad Sci USA 92:258–262
Lundblad V, Szostak JW (1989) A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57:633–643
McGrath M, Lee IM, Buring J, Hunter DJ, De Vivo I (2008) Novel breast cancer risk alleles and endometrial cancer risk. Int J Cancer 123:2961–2964
Mooi WJ, Peeper DS (2006) Oncogene-induced cell senescence—halting on the road to cancer. N Engl J Med 355:1037–1046
Nemes Z, Steinert PM (1999) Bricks and mortar of the epidermal barrier. Exp Mol Med 31:5–19
Pooley KA, Tyrer J, Shah M, Driver KE, Leyland J, Brown J, Audley T, McGuffog L, Ponder BA, Pharoah PD, Easton DF, Dunning AM (2010) No association between TERT-CLPTM1L single nucleotide polymorphism rs401681 and mean telomere length or cancer risk. Cancer Epidemiol Biomarkers Prev 19:1862–1865
Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, Jakobsdottir M, Helgadottir H, Thorlacius S, Aben KK, Blondal T, Thorgeirsson TE, Thorleifsson G, Kristjansson K, Thorisdottir K, Ragnarsson R, Sigurgeirsson B, Skuladottir H, Gudbjartsson T, Isaksson HJ, Einarsson GV, Benediktsdottir KR, Agnarsson BA, Olafsson K, Salvarsdottir A, Bjarnason H, Asgeirsdottir M, Kristinsson KT, Matthiasdottir S, Sveinsdottir SG, Polidoro S, Hoiom V, Botella-Estrada R, Hemminki K, Rudnai P, Bishop DT, Campagna M, Kellen E, Zeegers MP, de Verdier P, Ferrer A, Isla D, Vidal MJ, Andres R, Saez B, Juberias P, Banzo J, Navarrete S, Tres A, Kan D, Lindblom A, Gurzau E, Koppova K, de Vegt F, Schalken JA, van der Heijden HF, Smit HJ, Termeer RA, Oosterwijk E, van Hooij O, Nagore E, Porru S, Steineck G, Hansson J, Buntinx F, Catalona WJ, Matullo G, Vineis P, Kiltie AE, Mayordomo JI, Kumar R, Kiemeney LA, Frigge ML, Jonsson T, Saemundsson H, Barkardottir RB, Jonsson E, Jonsson S, Olafsson JH, Gulcher JR, Masson G, Gudbjartsson DF, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 41:221–227
Smith S, de Lange T (2000) Tankyrase promotes telomere elongation in human cells. Curr Biol 10:1299–1302
van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413
Wai LK (2004) Telomeres, telomerase, and tumorigenesis—a review. Med Gen Med 6:19
Acknowledgments
We thank Dr. Hardeep Ranu and Ms. Pati Soule of the Dana-Farber/Harvard Cancer Center High-Throughput Polymorphism Detection Core for their laboratory assistance, and Ms. Carolyn Guo for her programming support. We are indebted to the participants in the Nurses’ Health Study for their dedication and commitment. This work was supported by National Institutes of Health research grants CA122838, CA133914, CA082838, and CA132190. JP was supported by NIH training grant 5T32 CA 09001.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Nan, H., Qureshi, A.A., Prescott, J. et al. Genetic variants in telomere-maintaining genes and skin cancer risk. Hum Genet 129, 247–253 (2011). https://doi.org/10.1007/s00439-010-0921-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-010-0921-5