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- Title
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
- Authors
Bojesen, Stig E; Lu, Yi; Chen, Xiaoqing; Healey, Sue; Spurdle, Amanda B; Cramer, Daniel W; Terry, Kathryn L; Vitonis, Allison F; van der Schoot, C Ellen; Poole, Elizabeth M; Tworoger, Shelley S; Hogervorst, Frans B L; Liu, Jianjun; Li, Jingmei; Bandera, Elisa V; Rodriguez-Rodriguez, Lorna; Olson, Sara H; Orlow, Irene; Blomqvist, Carl; Aittomäki, Kristiina
- 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.
- Subjects
TELOMERASE reverse transcriptase; TELOMERES; BREAST cancer risk factors; OVARIAN cancer; SINGLE nucleotide polymorphisms; BRCA genes; LEUCOCYTES; CANCER risk factors
- Publication
Nature Genetics, 2013, Vol 45, Issue 4, p371
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2566