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

Article, Other literature type English OPEN
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 ; Smart, Chanel E ; Hillman, Kristine M ; Mai, Phuong L ; Lawrenson, Kate ; Stutz, Michael D ; Lu, Yi ; Karevan, Rod ; Woods, Nicholas ; Johnston, Rebecca L ; French, Juliet D ; Chen, Xiaoqing ; Weischer, Maren ; Nielsen, Sune F ; Maranian, Melanie J ; Ghoussaini, Maya ; Ahmed, Shahana ; Baynes, Caroline ; Bolla, Manjeet K ; Wang, Qin ; Dennis, Joe ; McGuffog, Lesley ... view all 437 authors (2013)
  • Publisher: Nature Publishing Group
  • Journal: volume 45, issue 4, pages 371-384 (issn: 1061-4036, eissn: 1546-1718)
  • Related identifiers: doi: 10.1038/ng.2566., doi: 10.1038/ng.2566
  • Subject: Càncer d'ovari | Ovarian cancer | Telomere | Breast cancer | Càncer de mama | Telòmer | Article

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.