Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
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Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. / Bojesen, Stig E; Pooley, Karen A; Johnatty, Sharon E; Beesley, Jonathan; Michailidou, Kyriaki; Tyrer, Jonathan P; Edwards, Stacey L; Pickett, Hilda A; Shen, Howard C; Smart, Chanel E; Hillman, Kristine M; Mai, Phuong L; Lawrenson, Kate; Stutz, Michael D; Lu, Yi; Karevan, Rod; Woods, Nicholas; Johnston, Rebecca L; French, Juliet D; Chen, Xiaoqing; Weischer, Maren; Nielsen, Sune F; Maranian, Melanie J; Ghoussaini, Maya; Ahmed, Shahana; Baynes, Caroline; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew Roger; Healey, Sue; Lush, Michael; Tessier, Daniel C; Vincent, Daniel; Bacot, Françis; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Risch, Harvey A; González-Neira, Anna; Rossing, Mary Anne; Pita, Guillermo; Doherty, Jennifer A; Alvarez, Nuria; Nordestgaard, Børge G; Engelholm, Svend Aage; Høgdall, Claus K; Gerdes, Anne-Marie; Australian Cancer Study.
I: Nature Genetics, Bind 45, Nr. 4, 04.2013, s. 371-84, 384e1-2.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 - Johnston, 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 Roger
AU - Healey, Sue
AU - Lush, Michael
AU - Tessier, Daniel C
AU - Vincent, Daniel
AU - Bacot, Françis
AU - Vergote, Ignace
AU - Lambrechts, Sandrina
AU - Despierre, Evelyn
AU - Risch, Harvey A
AU - González-Neira, Anna
AU - Rossing, Mary Anne
AU - Pita, Guillermo
AU - Doherty, Jennifer A
AU - Alvarez, Nuria
AU - Nordestgaard, Børge G
AU - Engelholm, Svend Aage
AU - Høgdall, Claus K
AU - Gerdes, Anne-Marie
AU - Australian Cancer Study
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 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.
AB - 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.
U2 - 10.1038/ng.2566
DO - 10.1038/ng.2566
M3 - Journal article
C2 - 23535731
VL - 45
SP - 371-84, 384e1-2
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -
ID: 48443121