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.
Source: Multiple independent variants at the TERT locus are
associated with telomere length and risks of breast and ovarian cancer. Bojesen
SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL,
Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL , Lawrenson K, Stutz MD, Lu Y, Karevan R,
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Australian Cancer Study; Australian Ovarian Cancer Study; Kathleen Cuningham
Foundation Consortium for Research into Familial Breast Cancer (kConFab); Gene
Environment Interaction and Breast Cancer (GENICA); Swedish Breast Cancer Study
(SWE-BRCA); Hereditary Breast and Ovarian Cancer Research Group Netherlands
(HEBON); Epidemiological study of BRCA1 & BRCA2 Mutation Carriers
(EMBRACE); Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO),
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