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

Journal 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.

Authors: Bojesen, SE; Pooley, K; Johnatty, SE; Beesley, J; Michailidou, K

• Publication status: Published
• Journal: Nature genetics
• Volume: 45
• Issue: 4
• Pages: 371-384e2
• Publication date: 2013-04-01
• DOI: 10.1038/ng.2566
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Gene Environment Interaction and Breast Cancer (GENICA); Genotype; Ovarian Neoplasms; Real-Time Polymerase Chain Reaction; Australian Ovarian Cancer Study; Tumor Markers, Biological; Epidemiological study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE); Breast Neoplasms; Female; Alternative Splicing; DNA Methylation; Case-Control Studies; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab); Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Reverse Transcriptase Polymerase Chain Reaction; Chromatin; RNA, Messenger; Swedish Breast Cancer Study (SWE-BRCA); Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO); Genetic Loci; Risk Factors; Telomere; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Luciferases; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON); Gene Expression Profiling; Telomerase; Australian Cancer Study