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

Publication ,  Journal Article
Bojesen, SE; Pooley, KA; Johnatty, SE; Beesley, J; Michailidou, K; Tyrer, JP; Edwards, SL; Pickett, HA; Shen, HC; Smart, CE; Hillman, KM ...
Published in: Nat Genet
April 2013

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.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2013

Volume

45

Issue

4

Start / End Page

371 / 384e2

Location

United States

Related Subject Headings

  • Telomere
  • Telomerase
  • Risk Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oligonucleotide Array Sequence Analysis
  • Luciferases
 

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Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., … Dunning, A. M. (2013). Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet, 45(4), 371-384e2. https://doi.org/10.1038/ng.2566
Bojesen, Stig E., Karen A. Pooley, Sharon E. Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P. Tyrer, Stacey L. Edwards, et al. “Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.Nat Genet 45, no. 4 (April 2013): 371-384e2. https://doi.org/10.1038/ng.2566.
Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013 Apr;45(4):371-384e2.
Bojesen, Stig E., et al. “Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.Nat Genet, vol. 45, no. 4, Apr. 2013, pp. 371-384e2. Pubmed, doi:10.1038/ng.2566.
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, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, 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), Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, 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Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea M-K, Paluch SS, Laitman Y, Skytte A-B, Kruse TA, Jensen UB, Robson M, Gerdes A-M, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro ANA, Gayther SA, Pharoah PDP, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, Dunning AM. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013 Apr;45(4):371-384e2.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2013

Volume

45

Issue

4

Start / End Page

371 / 384e2

Location

United States

Related Subject Headings

  • Telomere
  • Telomerase
  • Risk Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oligonucleotide Array Sequence Analysis
  • Luciferases