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

Bojesen, S.E. and Pooley, K.A. and Johnatty, S.E. and Beesley, J. and Michailidou, K. and Tyrer, J.P. and Edwards, S.L. and Pickett, H.A. and Shen, H.C. and Smart, C.E. and Hillman, K.M. and Mai, P.L. and Lawrenson, K. and Stutz, M.D. and Lu, Y. and Karevan, R. and Woods, N. and Johnstonw, R.L. and French, J.D. and Chen, X.Q. and Weischer, M. and Nielsen, S.F. and Maranian, M.J. and Ghoussaini, M. and Ahmed, S. and Baynes, C. and Bolla, M.K. and Wang, Q. and Dennis, J. and McGuffog, L. and Barrowdale, D. and Lee, A. and Healey, S. and Lush, M. and Tessier, D.C. and Vincent, D. and Bacot, F. and Vergote, I. and Lambrechts, S. and Despierre, E. and Risch, H.A. and Gonzaalez-Neira, A. and Rossing, M.A. and Pita, G. and Doherty, J.A. and Alvarez, N. and Larson, M.C. and Fridley, B.L. and Schoof, N. and Chang-Claude, J. and Cicek, M.S. and Peto, J. and Kalli, K.R. and Broeks, A. and Armasu, S.M. and Schmidt, M.K. and Braaf, L.M. and Winterhoff, B. and Nevanlinna, H. and Konecny, G.E. and Lambrechts, D. and Rogmann, L. and Guenel, P. and Teoman, A. and Milne, R.L. and Garcia, J.J. and Cox, A. and Shridhar, V. and Burwinkel, B. and Marme, F. and Hein, R. and Sawyer, E.J. and Haiman, C.A. and Wang-Gohrke, S. and Andrulis, I.L. and Moysich, K.B. and Hopper, J.L. and Odunsi, K. and Lindblom, A. and Giles, G.G. and Brenner, H. and Simard, J. and Lurie, G. and Fasching, P.A. and Carney, M.E. and Radice, P. and Wilkens, L.R. and Swerdlow, A. and Goodman, M.T. and Brauch, H. and Garcia-Closas, M. and Hillemanns, P. and Winqvist, R. and Durst, M. and Devilee, P. and Runnebaum, I. and Jakubowska, A. and Lubinski, J. and Mannermaa, A. and Butzow, R. and Omar, S.Z. (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. ISSN 1061-4036

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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.

Item Type: Article
Uncontrolled Keywords: Genome-wide association; reverse-transcriptase htert; susceptibility; loci; tert-clptm1l locus; genetic-variation; common variants; buccal; cells; fibroblasts; carcinoma; metaanalysis
Subjects: R Medicine
R Medicine > RG Gynecology and obstetrics
Divisions: Faculty of Medicine
Depositing User: Ms Haslinda Lahuddin
Date Deposited: 16 Jul 2014 01:12
Last Modified: 21 Dec 2014 08:08
URI: http://eprints.um.edu.my/id/eprint/10835

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