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

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; Johnston, 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; González-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; Guénel, P; Teoman, A; Milne, RL; Garcia, JJ; Cox, A; 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; 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Humphreys, K; Orlow, I; Blomqvist, C; Rodríguez-Rodríguez, L; Aittomäki, 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, LF; Benitez, J; Pejovic, T; Pérez, JI; Hoatlin, M; Zamora, MP; Cook, LS; Balasubramanian, SP; 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; Le Marchand, L; Yang, HP; Mulligan, AM; Glendon, G; Engelholm, SA; Knight, JA; Høgdall, CK; Apicella, C; Gore, M; Tsimiklis, H; Song, H; Southey, MC; Jager, A; den Ouweland, AM; Brown, R; Martens, JW; Flanagan, JM; Kriege, M; Paul, J; Margolin, S; Siddiqui, N; Severi, G; Whittemore, AS; Baglietto, L; McGuire, V; Stegmaier, C; Sieh, W; Muller, H; Arndt, V; Labrèche, F; Gao, YT; 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; Bruning, T; Pike, MC; Ko, YD; Lissowska, J; Figueroa, J; Kupryjanczyk, J; Chanock, SJ; Dansonka-Mieszkowska, A; Jukkola-Vuorinen, A; Rzepecka, IK; Pylkäs, K; Bidzinski, M; Kauppila, S; Hollestelle, A; Seynaeve, C; Tollenaar, RA; Durda, K; Jaworska, K; Hartikainen, JM; Kosma, VM; 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, CC; Stram, DO; Van Den Berg, D; Yip, CH; Ikram, MK; Teh, YC; Cai, H; Lu, W; Signorello, LB; Cai, Q; Noh, DY; Yoo, KY; Miao, H; Iau, PT; Teo, YY; McKay, J; Shapiro, C; Ademuyiwa, F; Fountzilas, G; Hsiung, CN; Yu, JC; Hou, MF; Healey, CS; Luccarini, C; Peock, S; Stoppa-Lyonnet, D; Peterlongo, P; Rebbeck, TR; Piedmonte, M; Singer, CF; Friedman, E; Thomassen, M; 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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; Johnston, 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; González-Neira...     »

TERT-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 TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 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 (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 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 splice variant.     «

TERT-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 TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 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 wi...     »