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

Abstract

TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splicevariant

Metadata

Item Type:	Article
Authors/Creators:	Bojesen, SE Pooley, KA Johnatty, SE Beesley, J Michailidou, K Tyrer, JP Edwards, SL Pickett, HA Shen, HC Smart, CE Hillman, KM Mai, PL Lawrenson, K Stutz, MD Lu, Y Karevan, R Woods, N Johnstonw, RL French, JD Chen, X Weischer, M Nielsen, SF Maranian, MJ Ghoussaini, M Ahmed, S Baynes, C Bolla, MK Wang, Q Dennis, J McGuffog, L Barrowdale, D Lee, A Healey, S Lush, M Tessier, DC Vincent, D Bacot, F Vergote, I Lambrechts, S Despierre, E Risch, HA Gonzalez-Neira, A Rossing, MA Pita, G Doherty, JA Alvarez, N Larson, MC Fridley, BL Schoof, N Chang-Claude, J Cicek, MS Peto, J Kalli, KR Broeks, A Armasu, SM Schmidt, MK Braaf, LM Winterhoff, B Nevanlinna, H Konecny, GE Lambrechts, D Rogmann, L Guenel, P Teoman, A Milne, RL Garcia, JJ Cox, A https://orcid.org/0000-0002-5138-1099 Shridhar, V Burwinkel, B Marme, F Hein, R Sawyer, EJ Haiman, CA Wang-Gohrke, S Andrulis, IL Moysich, KB Hopper, JL Odunsi, K Lindblom, A Giles, GG Brenner, H Simard, J Lurie, G Fasching, PA Carney, ME Radice, P Wilkens, LR Swerdlow, A Goodman, MT Brauch, H Garcia-Closas, M Hillemanns, P Winqvist, R Durst, M Devilee, P Runnebaum, I Jakubowska, A Lubinski, J Mannermaa, A Butzow, R Bogdanova, NV Doerk, T Pelttari, LM Zheng, W Leminen, A Anton-Culver, H Bunker, CH Kristensen, V Ness, RB Muir, K Edwards, R Meindl, A Heitz, F Matsuo, K du Bois, A Wu, AH 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, BY Sangrajrang, S Kjaer, SK Gaborieau, V Jensen, A Eccles, D Hogdall, E Shen, C-Y Brown, J Woo, YL Shah, M Azmi, MAN Luben, R Omar, SZ Czene, K Vierkant, RA Nordestgaard, BG Flyger, H Vachon, C Olson, JE Wang, X Levine, DA Rudolph, A Weber, RP Flesch-Janys, D Iversen, E Nickels, S Schildkraut, JM Silva, IDS Cramer, DW Gibson, L Terry, KL Fletcher, O Vitonis, AF van der Schoot, CE Poole, EM Hogervorst, FBL Tworoger, SS Liu, J Bandera, EV Li, J Olson, SH Humphreys, K Row, I Blomqvist, C Rodriguez-Rodriguez, L Aittomaki, K Salvesen, HB Muranen, TA Wik, E Brouwers, B Krakstad, C Wauters, E Halle, MK Wildiers, H Kiemeney, LA Mulot, C Aben, KK Laurent-Puig, P Altena, AM Truong, T Massuger, LFAG Benitez, J Pejovic, T Arias Perez, JI Hoatlin, M Zamora, MP Cook, LS Balasubramanian, SP https://orcid.org/0000-0001-5953-2843 Kelemen, LE Schneeweiss, A Le, ND Sohn, C Brooks-Wilson, A Tomlinson, I Kerin, MJ Miller, N Cybulski, C Henderson, BE Menkiszak, J Schumacher, F Wentzensen, N Marchand, LL Yang, HP Mulligan, AM Glendon, G Engelholm, SA Knight, JA Hogdall, CK Apicella, C Gore, M Tsimiklis, H Song, H Southey, MC Jager, A den Ouweland, AMW Brown, R Martens, JWM Flanagan, JM Kriege, M Paul, J Margolin, S Siddiqui, N Severi, G Whittemore, AS Baglietto, L McGuire, V Stegmaier, C Sieh, W Mueller, H Arndt, V Labreche, F Gao, Y-T Goldberg, MS Yang, G Dumont, M McLaughlin, JR Hartmann, A Ekici, AB Beckmann, MW Phelan, CM Lux, MP Permuth-Wey, J Peissel, B Sellers, TA Ficarazzi, F Barile, M Ziogas, A Ashworth, A Gentry-Maharaj, A Jones, M Ramus, SJ Orr, N Menon, U Pearce, CL Bruening, T Pike, MC Ko, Y-D Lissowska, J Figueroa, J Kupryjanczyk, J Chanock, SJ Dansonka-Mieszkowska, A Jukkola-Vuorinen, A Rzepecka, IK Pylkas, K Bidzinski, M Kauppila, S Hollestelle, A Seynaeve, C Tollenaar, RAEM Durda, K Jaworska, K Hartikainen, JM Kosma, V-M Kataja, V Antonenkova, NN Long, J Shrubsole, M Deming-Halverson, S Lophatananon, A Siriwanarangsan, P Stewart-Brown, S Ditsch, N Lichtner, P Schmutzler, RK Ito, H Iwata, H Tajima, K Tseng, C-C Stram, DO van den Berg, D Yip, CH Ikrarn, MK Teh, Y-C Cai, H Lu, W Signorello, LB Cai, Q Noh, D-Y Yoo, K-Y Miao, H Iau, PT-C Teo, YY McKay, J Shapiro, C Ademuyiwa, F Fountzilas, G Hsiung, C-N Yu, J-C Hou, M-F Healey, CS Luccarini, C Peock, S Stoppa-Lyonnet, D Peterlongo, P Rebbeck, TR Piedmonte, M Singer, CF Friedman, E Thomassen, M Offit, K Hansen, TVO Neuhausen, SL Szabo, CI Blanco, I Garber, J Narod, SA Weitzel, JN Montagna, M Olah, E Godwin, AK Yannoukakos, D Goldgar, DE Caldes, T Imyanitov, EN Tihomirova, L Arun, BK Campbell, I Mensenkamp, AR van Asperen, CJ van Roozendaa, KEP Meijers-Heijboer, H Collee, JM Oosterwijk, JC Hooning, MJ Rookus, MA van der Luijt, RB Os, TAM Evans, DG Frost, D Fineberg, E Barwell, J Walker, L Kennedy, MJ Platte, R Davidson, R Ellis, SD Cole, T Bressac-de Paillerets, B Buecher, B Damiola, F Faivre, L Frenay, M Sinilnikova, OM Caron, O Giraud, S Mazoyer, S Bonadona, V Caux-Moncoutier, V Toloczko-Grabarek, A Gronwald, J Byrski, T Spurdle, AB Bonanni, B Zaffaroni, D Giannini, G Bernard, L Dolcetti, R Manoukian, S Arnold, N Engel, C Deissler, H Rhiem, K Niederacher, D Pendl, H Sutter, C Wappenschmidt, B Borg, A Mein, B Rantala, J Soller, M Nathanson, KL Domchek, SM Rodriguez, GC Salani, R Kaulich, DG Tea, M-K Paluch, SS Laitman, Y Skytte, A-B Kruse, TA Jensen, UB Robson, M Gerdes, A-M Ejlertsen, B Foretova, L Savage, SA Lesterm, J Soucy, P Kuchenbaecker, KB Olswold, C Cunningham, JM Slager, S Pankratz, VS Dicks, E Lakhani, SR Couch, FJ Hall, P Monteiro, ANA Gayther, SA Pharoah, PDP Reddel, RR Goode, EL Greene, MH Easton, DF Berchuck, A Antoniou, AC Chenevix-Trench, G Dunning, AM Study, AC Study, AOC Consortium, KCF Breast, GEI SWE-BRCA, SBCS Res, HBOC BRCA1, ES BRCA1, GMCR
Copyright, Publisher and Additional Information:	© 2013 Nature Publishing Group. This is an author produced version of a paper subsequently published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Accepted: 31 January 2013 Published (online): 2013 Published: 27 March 2013
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	20 Jan 2017 15:54
Last Modified:	21 Mar 2018 08:51
Published Version:	https://doi.org/10.1038/ng.2566
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/ng.2566
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:110838

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

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