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

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.; Johnstonw, R.L.; French, J.D.; Chen, X.Q.; 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.; Gonzaalez-Neira, A.; Rossing, M.A.; Pita, G.; Doherty, J.A.; Alvarez, 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.; Guenel, 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.; Durst, M.; Devilee, P.; Runnebaum, I.; Jakubowska, A.; Lubinski, J.; Mannermaa, A.; Butzow, R.; 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
Creators:
  1. Bojesen, S.E.
  2. Pooley, K.A.
  3. Johnatty, S.E.
  4. Beesley, J.
  5. Michailidou, K.
  6. Tyrer, J.P.
  7. Edwards, S.L.
  8. Pickett, H.A.
  9. Shen, H.C.
  10. Smart, C.E.
  11. Hillman, K.M.
  12. Mai, P.L.
  13. Lawrenson, K.
  14. Stutz, M.D.
  15. Lu, Y.
  16. Karevan, R.
  17. Woods, N.
  18. Johnstonw, R.L.
  19. French, J.D.
  20. Chen, X.Q.
  21. Weischer, M.
  22. Nielsen, S.F.
  23. Maranian, M.J.
  24. Ghoussaini, M.
  25. Ahmed, S.
  26. Baynes, C.
  27. Bolla, M.K.
  28. Wang, Q.
  29. Dennis, J.
  30. McGuffog, L.
  31. Barrowdale, D.
  32. Lee, A.
  33. Healey, S.
  34. Lush, M.
  35. Tessier, D.C.
  36. Vincent, D.
  37. Bacot, F.
  38. Vergote, I.
  39. Lambrechts, S.
  40. Despierre, E.
  41. Risch, H.A.
  42. Gonzaalez-Neira, A.
  43. Rossing, M.A.
  44. Pita, G.
  45. Doherty, J.A.
  46. Alvarez, N.
  47. Larson, M.C.
  48. Fridley, B.L.
  49. Schoof, N.
  50. Chang-Claude, J.
  51. Cicek, M.S.
  52. Peto, J.
  53. Kalli, K.R.
  54. Broeks, A.
  55. Armasu, S.M.
  56. Schmidt, M.K.
  57. Braaf, L.M.
  58. Winterhoff, B.
  59. Nevanlinna, H.
  60. Konecny, G.E.
  61. Lambrechts, D.
  62. Rogmann, L.
  63. Guenel, P.
  64. Teoman, A.
  65. Milne, R.L.
  66. Garcia, J.J.
  67. Cox, A.
  68. Shridhar, V.
  69. Burwinkel, B.
  70. Marme, F.
  71. Hein, R.
  72. Sawyer, E.J.
  73. Haiman, C.A.
  74. Wang-Gohrke, S.
  75. Andrulis, I.L.
  76. Moysich, K.B.
  77. Hopper, J.L.
  78. Odunsi, K.
  79. Lindblom, A.
  80. Giles, G.G.
  81. Brenner, H.
  82. Simard, J.
  83. Lurie, G.
  84. Fasching, P.A.
  85. Carney, M.E.
  86. Radice, P.
  87. Wilkens, L.R.
  88. Swerdlow, A.
  89. Goodman, M.T.
  90. Brauch, H.
  91. Garcia-Closas, M.
  92. Hillemanns, P.
  93. Winqvist, R.
  94. Durst, M.
  95. Devilee, P.
  96. Runnebaum, I.
  97. Jakubowska, A.
  98. Lubinski, J.
  99. Mannermaa, A.
  100. Butzow, R.
  101. Omar, S.Z.(Department of Obstetric and Gynaecology, Faculty of Medicine Building, University of Malaya, 50603 Kuala Lumpur, MALAYSIA)
Journal or Publication Title: Nature Genetics
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 09:12
Last Modified: 21 Dec 2014 16:08
URI: http://eprints.um.edu.my/id/eprint/10835

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