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

TitleMultiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsBojesen, S. E., Pooley K. A., Johnatty S. E., Beesley J., Michailidou K., Tyrer J. P., et al.
Corporate AuthorsAustralian 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)
JournalNat Genet
Volume45
Issue4
Pagination371-84, 384e1-2
Date Published2013 Apr
ISSN1546-1718
KeywordsAlternative 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.

DOI10.1038/ng.2566
Alternate JournalNat. Genet.
PubMed ID23535731
PubMed Central IDPMC3670748
Grant List076113 / / 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

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