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

Nat Genet. 2013 Apr;45(4):371-84, 384e1-2. doi: 10.1038/ng.2566.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Chromatin / genetics
  • DNA Methylation
  • Female
  • Gene Expression Profiling
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Luciferases / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Ovarian Neoplasms / etiology*
  • Ovarian Neoplasms / pathology
  • Polymorphism, Single Nucleotide / genetics*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Telomerase / genetics*
  • Telomere / genetics*

Substances

  • Biomarkers, Tumor
  • Chromatin
  • RNA, Messenger
  • Luciferases
  • TERT protein, human
  • Telomerase

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