TY - JOUR
T1 - Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
AU - Bojesen, Stig E.
AU - Pooley, Karen A.
AU - Johnatty, Sharon E.
AU - Beesley, Jonathan
AU - Michailidou, Kyriaki
AU - Tyrer, Jonathan P.
AU - Edwards, Stacey L.
AU - Pickett, Hilda A.
AU - Shen, Howard C.
AU - Smart, Chanel E.
AU - Hillman, Kristine M.
AU - Mai, Phuong L.
AU - Lawrenson, Kate
AU - Stutz, Michael D.
AU - Lu, Yi
AU - Karevan, Rod
AU - Woods, Nicholas
AU - Johnstonw, Rebecca L.
AU - French, Juliet D.
AU - Chen, Xiaoqing
AU - Weischer, Maren
AU - Nielsen, Sune F.
AU - Maranian, Melanie J.
AU - Ghoussaini, Maya
AU - Ahmed, Shahana
AU - Baynes, Caroline
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dennis, Joe
AU - McGuffog, Lesley
AU - Barrowdale, Daniel
AU - Lee, Andrew
AU - Healey, Sue
AU - Lush, Michael
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francis
AU - Vergote, Ignace
AU - Lambrechts, Sandrina
AU - Despierre, Evelyn
AU - Risch, Harvey A.
AU - Gonzalez-Neira, Anna
AU - Rossing, Mary Anne
AU - Pita, Guillermo
AU - Doherty, Jennifer A.
AU - Alvarez, Nuria
AU - Larson, Melissa C.
AU - Fridley, Brooke L.
AU - Schoof, Nils
AU - Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)
AU - van Roozendaal, Kees
PY - 2013/4
Y1 - 2013/4
N2 - TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 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 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 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 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 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.
AB - TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 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 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 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 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 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.
U2 - 10.1038/ng.2566
DO - 10.1038/ng.2566
M3 - Article
C2 - 23535731
SN - 1061-4036
VL - 45
SP - 371
EP - 384
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -