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

Bojesen, Stig E.; Pooley, Karen A.; Johnatty, Sharon E.; Beesley, Jonathan; Michailidou, Kyriaki; Tyrer, Jonathan P.; Edwards, Stacey L.; Pickett, Hilda A.; Shen, Howard C. and Smart, Chanel E., et al. (2013) In Nature Genetics 45(4). p.371-384
Abstract
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 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 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP... (More)
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 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 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 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 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 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. (Less)
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Nature Genetics
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45
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4
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371 - 384
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Nature Publishing Group
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  • scopus:84875717832
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1546-1718
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10.1038/ng.2566
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English
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ff454645-43d6-4a34-8d7c-16e609a54709 (old id 3748554)
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@article{ff454645-43d6-4a34-8d7c-16e609a54709,
  abstract     = {TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 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 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 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 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 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.},
  author       = {Bojesen, Stig E. and Pooley, Karen A. and Johnatty, Sharon E. and Beesley, Jonathan and Michailidou, Kyriaki and Tyrer, Jonathan P. and Edwards, Stacey L. and Pickett, Hilda A. and Shen, Howard C. and Smart, Chanel E. and Hillman, Kristine M. and Mai, Phuong L. and Lawrenson, Kate and Stutz, Michael D. and Lu, Yi and Karevan, Rod and Woods, Nicholas and Johnstonw, Rebecca L. and French, Juliet D. and Chen, Xiaoqing and Weischer, Maren and Nielsen, Sune F. and Maranian, Melanie J. and Ghoussaini, Maya and Ahmed, Shahana and Baynes, Caroline and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and McGuffog, Lesley and Barrowdale, Daniel and Lee, Andrew and Healey, Sue and Lush, Michael and Tessier, Daniel C. and Vincent, Daniel and Bacot, Francis and Vergote, Ignace and Lambrechts, Sandrina and Despierre, Evelyn and Risch, Harvey A. and Gonzalez-Neira, Anna and Rossing, Mary Anne and Pita, Guillermo and Doherty, Jennifer A. and Alvarez, Nuria and Larson, Melissa C. and Fridley, Brooke L. and Schoof, Nils and Chang-Claude, Jenny and Cicek, Mine S. and Peto, Julian and Kalli, Kimberly R. and Broeks, Annegien and Armasu, Sebastian M. and Schmidt, Marjanka K. and Braaf, Linde M. and Winterhoff, Boris and Nevanlinna, Heli and Konecny, Gottfried E. and Lambrechts, Diether and Rogmann, Lisa and Guenel, Pascal and Teoman, Attila and Milne, Roger L. and Garcia, Joaquin J. and Cox, Angela and Shridhar, Vijayalakshmi and Burwinkel, Barbara and Marme, Frederik and Hein, Rebecca and Sawyer, Elinor J. and Haiman, Christopher A. and Wang-Gohrke, Shan and Andrulis, Irene L. and Moysich, Kirsten B. and Hopper, John L. and Odunsi, Kunle and Lindblom, Annika and Giles, Graham G. and Brenner, Hermann and Simard, Jacques and Lurie, Galina and Fasching, Peter A. and Carney, Michael E. and Radice, Paolo and Wilkens, Lynne R. and Swerdlow, Anthony and Goodman, Marc T. and Brauch, Hiltrud and Garcia-Closas, Montserrat and Hillemanns, Peter and Winqvist, Robert and Durst, Matthias and Devilee, Peter and Runnebaum, Ingo and Jakubowska, Anna and Lubinski, Jan and Mannermaa, Arto and Butzow, Ralf and Bogdanova, Natalia V. and Doerk, Thilo and Pelttari, Liisa M. and Zheng, Wei and Leminen, Arto and Anton-Culver, Hoda and Bunker, Clareann H. and Kristensen, Vessela and Ness, Roberta B. and Muir, Kenneth and Edwards, Robert and Meindl, Alfons and Heitz, Florian and Matsuo, Keitaro and du Bois, Andreas and Wu, Anna H. and Harter, Philipp and Teo, Soo-Hwang and Schwaab, Ira and Shu, Xiao-Ou and Blot, William and Hosono, Satoyo and Kang, Daehee and Nakanishi, Toru and Hartman, Mikael and Yatabe, Yasushi and Hamann, Ute and Karlan, Beth Y. and Sangrajrang, Suleeporn and Kjaer, Susanne Kruger and Gaborieau, Valerie and Jensen, Allan and Eccles, Diana and Hogdall, Estrid and Shen, Chen-Yang and Brown, Judith and Woo, Yin Ling and Shah, Mitul and Azmi, Mat Adenan Noor and Luben, Robert and Omar, Siti Zawiah and Czene, Kamila and Vierkant, Robert A. and Nordestgaard, Borge G. and Flyger, Henrik and Vachon, Celine and Olson, Janet E. and Wang, Xianshu and Levine, Douglas A. and Rudolph, Anja and Weber, Rachel Palmieri and Flesch-Janys, Dieter and Iversen, Edwin and Nickels, Stefan and Schildkraut, Joellen M. and Silva, Isabel Dos Santos and Cramer, Daniel W. and Gibson, Lorna and Terry, Kathryn L. and Fletcher, Olivia and Vitonis, Allison F. and van der Schoot, C. Ellen and Poole, Elizabeth M. and Hogervorst, Frans B. L. and Tworoger, Shelley S. and Liu, Jianjun and Bandera, Elisa V. and Li, Jingmei and Olson, Sara H. and Humphreys, Keith and Row, Irene and Blomqvist, Carl and Rodriguez-Rodriguez, Lorna and Aittomaki, Kristiina and Salvesen, Helga B. and Muranen, Taru A. and Wik, Elisabeth and Brouwers, Barbara and Krakstad, Camilla and Wauters, Els and Halle, Mari K. and Wildiers, Hans and Kiemeney, Lambertus A. and Mulot, Claire and Aben, Katja K. and Laurent-Puig, Pierre and Altena, Anne Mvan and Truong, Therese and Massuger, Leon F. A. G. and Benitez, Javier and Pejovic, Tanja and Arias Perez, Jose Ignacio and Hoatlin, Maureen and Zamora, M. 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  issn         = {1546-1718},
  language     = {eng},
  number       = {4},
  pages        = {371--384},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer},
  url          = {http://dx.doi.org/10.1038/ng.2566},
  volume       = {45},
  year         = {2013},
}