Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Bojesen, S. E. et al. (2013) Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nature Genetics, 45(4), pp. 371-384. (doi:10.1038/ng.2566)

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Publisher's URL: http://dx.doi.org/10.1038/ng.2566

Abstract

<i>TERT</i>-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the <i>TERT</i> locus in breast (<i>n</i> = 103,991), ovarian (n = 39,774) and <i>BRCA1</i> mutation carrier (<i>n</i> = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (<i>P</i> = 5.8 × 10<sup>−7</sup>), lower risks for estrogen receptor (ER)-negative (<i>P</i> = 1.0 × 10<sup>−8</sup>) and <i>BRCA1</i> mutation carrier (<i>P</i> = 1.1 × 10<sup>−5</sup>) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (<i>P</i> = 2.3 × 10<sup>−14</sup>), higher risk of low-malignant-potential ovarian cancer (<i>P</i> = 1.3 × 10<sup>−15</sup>) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (<i>P</i> = 1.2 × 10<sup>−12</sup>) and <i>BRCA1</i> mutation carrier (<i>P</i> = 1.6 × 10<sup>−14</sup>) breast and invasive ovarian (<i>P</i> = 1.3 × 10<sup>−11</sup>) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated <i>TERT</i> splice variant.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paul, Mr James
Authors: Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., Edwards, S. L., Pickett, H. A., Shen, H. C., Smart, C. E., Hillman, K. M., Mai, P. L., Lawrenson, K., Stutz, M. D., Lu, Y., Karevan, R., Woods, N., Johnston, R. L., French, J. D., Chen, X., Weischer, M., Nielsen, S. F., Maranian, M. J., Ghoussaini, M., Ahmed, S., Baynes, C., Bolla, M. K., Wang, Q., Dennis, J., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Tessier, D. C., Vincent, D., Bacot, F., Vergote, I., Lambrechts, S., Despierre, E., Risch, H. A., González-Neira, A., Rossing, M. A., Pita, G., Doherty, J. A., Álvarez, N., Larson, M. C., Fridley, B. L., Schoof, N., Chang-Claude, J., Cicek, M. S., Peto, J., Kalli, K. R., Broeks, A., Armasu, S. M., Schmidt, M. K., Braaf, L. M., Winterhoff, B., Nevanlinna, H., Konecny, G. E., Lambrechts, D., Rogmann, L., Guénel, P., Teoman, A., Milne, R. L., Garcia, J. J., Cox, A., Shridhar, V., Burwinkel, B., Marme, F., Hein, R., Sawyer, E. J., Haiman, C. A., Wang-Gohrke, S., Andrulis, I. L., Moysich, K. B., Hopper, J. L., Odunsi, K., Lindblom, A., Giles, G. G., Brenner, H., Simard, J., Lurie, G., Fasching, P. A., Carney, M. E., Radice, P., Wilkens, L. R., Swerdlow, A., Goodman, M. T., Brauch, H., Garcia-Closas, M., Hillemanns, P., Winqvist, R., Dürst, M., Devilee, P., Runnebaum, I., Jakubowska, A., Lubinski, J., Mannermaa, A., Butzow, R., Bogdanova, N. V., Dörk, T., Pelttari, L. M., Zheng, W., Leminen, A., Anton-Culver, H., Bunker, C. H., Kristensen, V., Ness, R. B., Muir, K., Edwards, R., Meindl, A., Heitz, F., Matsuo, K., du Bois, A., Wu, A. H., Harter, P., Teo, S.-H., Schwaab, I., Shu, X.-O., Blot, W., Hosono, S., Kang, D., Nakanishi, T., Hartman, M., Yatabe, Y., Hamann, U., Karlan, B. Y., Sangrajrang, S., Kjaer, S. K., Gaborieau, V., Jensen, A., Eccles, D., Høgdall, E., Shen, C.-Y., Brown, J., Woo, Y. L., Shah, M., Azmi, M. A. N., Luben, R., Omar, S. Z., Czene, K., Vierkant, R. A., Nordestgaard, B. G., Flyger, H., Vachon, C., Olson, J. E., Wang, X., Levine, D. A., Rudolph, A., Weber, R. P., Flesch-Janys, D., Iversen, E., Nickels, S., Schildkraut, J. M., Silva, I. D. S., Cramer, D. W., Gibson, L., Terry, K. L., Fletcher, O., Vitonis, A. F., van der Schoot, C. E., Poole, E. M., Hogervorst, F. B. L., Tworoger, S. S., Liu, J., Bandera, E. V., Li, J., Olson, S. H., Humphreys, K., Orlow, I., Blomqvist, C., Rodriguez-Rodriguez, L., Aittomäki, K., Salvesen, H. B., Muranen, T. A., Wik, E., Brouwers, B., Krakstad, C., Wauters, E., Halle, M. K., Wildiers, H., Kiemeney, L. A., Mulot, C., Aben, K. K., Laurent-Puig, P., Altena, A. M., Truong, T., Massuger, L. F. A. G., Benitez, J., Pejovic, T., Perez, J. I. A., Hoatlin, M., Zamora, M. P., Cook, L. S., Balasubramanian, S. P., Kelemen, L. E., Schneeweiss, A., Le, N. D., Sohn, C., Brooks-Wilson, A., Tomlinson, I., Kerin, M. J., Miller, N., Cybulski, C., Henderson, B. E., Menkiszak, J., Schumacher, F., Wentzensen, N., Le Marchand, L., Yang, H. P., Mulligan, A. M., Glendon, G., Engelholm, S. A., Knight, J. A., Høgdall, C. K., Apicella, C., Gore, M., Tsimiklis, H., Song, H., Southey, M. C., Jager, A., den Ouweland, A. M. W., Brown, R., Martens, J. W. M., Flanagan, J. M., Kriege, M., Paul, J., Margolin, S., Siddiqui, N., Severi, G., Whittemore, A. S., Baglietto, L., McGuire, V., Stegmaier, C., Sieh, W., Müller, H., Arndt, V., Labrèche, F., Gao, Y.-T., Goldberg, M. S., Yang, G., Dumont, M., McLaughlin, J. R., Hartmann, A., Ekici, A. B., Beckmann, M. W., Phelan, C. M., Lux, M. P., Permuth-Wey, J., Peissel, B., Sellers, T. A., Ficarazzi, F., Barile, M., Ziogas, A., Ashworth, A., Gentry-Maharaj, A., Jones, M., Ramus, S. J., Orr, N., Menon, U., Pearce, C. L., Brüning, T., Pike, M. C., Ko, Y.-D., Lissowska, J., Figueroa, J., Kupryjanczyk, J., Chanock, S. J., Dansonka-Mieszkowska, A., Jukkola-Vuorinen, A., Rzepecka, I. K., Pylkäs, K., Bidzinski, M., Kauppila, S., Hollestelle, A., Seynaeve, C., Tollenaar, R. A. E. M., Durda, K., Jaworska, K., Hartikainen, J. M., Kosma, V.-M., Kataja, V., Antonenkova, N. N., Long, J., Shrubsole, M., Deming-Halverson, S., Lophatananon, A., Siriwanarangsan, P., Stewart-Brown, S., Ditsch, N., Lichtner, P., Schmutzler, R. K., Ito, H., Iwata, H., Tajima, K., Tseng, C.-C., Stram, D. O., van den Berg, D., Yip, C. H., Ikram, M. K., Teh, Y.-C., Cai, H., Lu, W., Signorello, L. B., Cai, Q., Noh, D.-Y., Yoo, K.-Y., Miao, H., Iau, P. T.-C., Teo, Y. Y., McKay, J., Shapiro, C., Ademuyiwa, F., Fountzilas, G., Hsiung, C.-N., Yu, J.-C., Hou, M.-F., Healey, C. S., Luccarini, C., Peock, S., Stoppa-Lyonnet, D., Peterlongo, P., Rebbeck, T. R., Piedmonte, M., Singer, C. F., Friedman, E., Thomassen, M., Offit, K., Hansen, T. V. O., Neuhausen, S. L., Szabo, C. I., Blanco, I., Garber, J., Narod, S. A., Weitzel, J. N., Montagna, M., Olah, E., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Imyanitov, E. N., Tihomirova, L., Arun, B. K., Campbell, I., Mensenkamp, A. R., van Asperen, C. J., van Roozendaal, K. E. P., Meijers-Heijboer, H., Collée, J. M., Oosterwijk, J. C., Hooning, M. J., Rookus, M. A., van der Luijt, R. B., Os, T. A. M., Evans, D. G., Frost, D., Fineberg, E., Barwell, J., Walker, L., Kennedy, M. J., Platte, R., Davidson, R., Ellis, S. D., Cole, T., Bressac-de Paillerets, B., Buecher, B., Damiola, F., Faivre, L., Frenay, M., Sinilnikova, O. M., Caron, O., Giraud, S., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Toloczko-Grabarek, A., Gronwald, J., Byrski, T., Spurdle, A. B., Bonanni, B., Zaffaroni, D., Giannini, G., Bernard, L., Dolcetti, R., Manoukian, S., Arnold, N., Engel, C., Deissler, H., Rhiem, K., Niederacher, D., Plendl, H., Sutter, C., Wappenschmidt, B., Borg, Å., Melin, B., Rantala, J., Soller, M., Nathanson, K. L., Domchek, S. M., Rodriguez, G. C., Salani, R., Kaulich, D. G., Tea, M.-K., Paluch, S. S., Laitman, Y., Skytte, A.-B., Kruse, T. A., Jensen, U. B., Robson, M., Gerdes, A.-M., Ejlertsen, B., Foretova, L., Savage, S. A., Lester, J., Soucy, P., Kuchenbaecker, K. B., Olswold, C., Cunningham, J. M., Slager, S., Pankratz, V. S., Dicks, E., Lakhani, S. R., Couch, F. J., Hall, P., Monteiro, A. N. A., Gayther, S. A., Pharoah, P. D. P., Reddel, R. R., Goode, E. L., Greene, M. H., Easton, D. F., Berchuck, A., Antoniou, A. C., Chenevix-Trench, G., and Dunning, A. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718

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