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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Stig E Bojesen
  • Karen A Pooley
  • Sharon E Johnatty
  • Jonathan Beesley
  • Kyriaki Michailidou
  • Jonathan P Tyrer
  • Stacey L Edwards
  • Hilda A Pickett
  • Howard C Shen
  • Chanel E Smart
  • Kristine M Hillman
  • Phuong L Mai
  • Kate Lawrenson
  • Michael D Stutz
  • Yi Lu
  • Rod Karevan
  • Nicholas Woods
  • Rebecca L Johnston
  • Juliet D French
  • Xiaoqing Chen
  • Maren Weischer
  • Sune F Nielsen
  • Melanie J Maranian
  • Maya Ghoussaini
  • Shahana Ahmed
  • Caroline Baynes
  • Manjeet K Bolla
  • Qin Wang
  • Joe Dennis
  • Lesley McGuffog
  • Daniel Barrowdale
  • Andrew Roger Lee
  • Sue Healey
  • Michael Lush
  • Daniel C Tessier
  • Daniel Vincent
  • Françis Bacot
  • Ignace Vergote
  • Sandrina Lambrechts
  • Evelyn Despierre
  • Harvey A Risch
  • Anna González-Neira
  • Mary Anne Rossing
  • Guillermo Pita
  • Jennifer A Doherty
  • Nuria Alvarez
  • Nordestgaard, Børge
  • Svend Aage Engelholm
  • Høgdall, Claus Kim
  • Gerdes, Anne-Marie Axø
  • Australian Cancer Study
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.
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind45
Udgave nummer4
Sider (fra-til)371-84, 384e1-2
ISSN1061-4036
DOI
StatusUdgivet - apr. 2013

ID: 48443121