Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Title | Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Bojesen, S. E., Pooley K. A., Johnatty S. E., Beesley J., Michailidou K., Tyrer J. P., et al. |
Corporate Authors | 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) |
Journal | Nat Genet |
Volume | 45 |
Issue | 4 |
Pagination | 371-84, 384e1-2 |
Date Published | 2013 Apr |
ISSN | 1546-1718 |
Keywords | Alternative Splicing, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, RNA, Messenger, Telomerase, Telomere, Tumor Markers, Biological |
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. |
DOI | 10.1038/ng.2566 |
Alternate Journal | Nat. Genet. |
PubMed ID | 23535731 |
PubMed Central ID | PMC3670748 |
Grant List | 076113 / / Wellcome Trust / United Kingdom 090532 / / Wellcome Trust / United Kingdom 10118 / / Cancer Research UK / United Kingdom 11022 / / Cancer Research UK / United Kingdom 11174 / / Cancer Research UK / United Kingdom 13086 / / Cancer Research UK / United Kingdom 15960 / / Cancer Research UK / United Kingdom C12292/A11174 / / Cancer Research UK / United Kingdom C1287/A10118 / / Cancer Research UK / United Kingdom C1287/A10710 / / Cancer Research UK / United Kingdom C1287/A12014 / / Cancer Research UK / United Kingdom C1287/A9540 / / Cancer Research UK / United Kingdom CA116201 / CA / NCI NIH HHS / United States CA128978 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States P30 CA016520 / CA / NCI NIH HHS / United States P30 ES013508 / ES / NIEHS NIH HHS / United States P50 CA116201 / CA / NCI NIH HHS / United States P50 CA136393 / CA / NCI NIH HHS / United States R01 CA083918 / CA / NCI NIH HHS / United States R01 CA092447 / CA / NCI NIH HHS / United States R01 CA122443 / CA / NCI NIH HHS / United States R01 CA128978 / CA / NCI NIH HHS / United States R01 CA149429 / CA / NCI NIH HHS / United States R37 CA070867 / CA / NCI NIH HHS / United States RC4 CA153828 / CA / NCI NIH HHS / United States / / Canadian Institutes of Health Research / Canada |