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

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. Johnstonw, Juliet D. French, Xiaoqing ChenMaren 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 Lee, Sue Healey, Michael Lush, Daniel C. Tessier, Daniel Vincent, Francis Bacot, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A. Risch, Anna Gonzalez-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A. Doherty, Nuria Alvarez, Melissa C. Larson, Brooke L. Fridley, Nils Schoof, Jan C. Oosterwijk, Australian Canc Study, Australian Ovarian Canc Study, Kathleen Cuningham Fdn Consortium, Gene Environm Interactimi Breast, Swedish Breast Canc Study SWE-BRCA, Hereditary Breast Ovarian Canc Res, Epidemiological Study BRCA1, Genetic Modifiers Canc Risk BRCA1

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

385 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)371-384
Number of pages14
JournalNature Genetics
Volume45
Issue number4
DOIs
Publication statusPublished - Apr-2013

Keywords

  • GENOME-WIDE ASSOCIATION
  • REVERSE-TRANSCRIPTASE HTERT
  • SUSCEPTIBILITY LOCI
  • TERT-CLPTM1L LOCUS
  • GENETIC-VARIATION
  • COMMON VARIANTS
  • BUCCAL CELLS
  • FIBROBLASTS
  • CARCINOMA
  • METAANALYSIS

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