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

被引：430

作者：

Bojesen, Stig E. ^{[1
,2
]}

Pooley, Karen A. ^{[3
]}

Johnatty, Sharon E. ^{[4
]}

Beesley, Jonathan ^{[4
]}

Michailidou, Kyriaki ^{[3
]}

Tyrer, Jonathan P. ^{[5
]}

Edwards, Stacey L. ^{[6
]}

Pickett, Hilda A. ^{[7
,8
]}

Shen, Howard C. ^{[9
]}

Smart, Chanel E. ^{[10
]}

Hillman, Kristine M. ^{[6
]}

Mai, Phuong L. ^{[11
]}

Lawrenson, Kate ^{[9
]}

Stutz, Michael D. ^{[7
,8
]}

Lu, Yi ^{[4
]}

Karevan, Rod ^{[9
]}

Woods, Nicholas ^{[12
]}

Johnston, Rebecca L. ^{[10
]}

French, Juliet D. ^{[6
]}

Chen, Xiaoqing ^{[4
]}

Weischer, Maren ^{[1
,2
]}

Nielsen, Sune F. ^{[1
,2
]}

Maranian, Melanie J. ^{[5
]}

Ghoussaini, Maya ^{[5
]}

Ahmed, Shahana ^{[5
]}

Baynes, Caroline ^{[5
]}

Bolla, Manjeet K. ^{[3
]}

Wang, Qin ^{[3
]}

Dennis, Joe ^{[3
]}

McGuffog, Lesley ^{[3
]}

Barrowdale, Daniel ^{[3
]}

Lee, Andrew ^{[3
]}

Healey, Sue ^{[4
]}

Lush, Michael ^{[3
]}

Tessier, Daniel C. ^{[13
,14
]}

Vincent, Daniel ^{[13
,14
]}

Bacot, Francis ^{[13
,14
]}

Vergote, Ignace ^{[15
,16
]}

Lambrechts, Sandrina ^{[15
,16
]}

Despierre, Evelyn ^{[15
,16
]}

Risch, Harvey A. ^{[17
,18
]}

Gonzalez-Neira, Anna ^{[19
]}

Rossing, Mary Anne ^{[20
,21
]}

Pita, Guillermo ^{[19
]}

Doherty, Jennifer A. ^{[22
]}

Alvarez, Nuria ^{[19
]}

Larson, Melissa C. ^{[23
]}

Fridley, Brooke L. ^{[24
]}

Schoof, Nils ^{[25
]}

Chang-Claude, Jenny ^{[26
]}

机构：

[1] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark

[2] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark

[3] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[4] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia

[5] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[6] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia

[7] Childrens Med Res Inst, Canc Res Unit, Westmead, NSW, Australia

[8] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia

[9] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[10] Univ Queensland, UQ Ctr Clin Res UQCCR, Royal Brisbane & Womens Hosp, Herston, Qld, Australia

[11] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Rockville, MD USA

[12] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA

[13] McGill Univ, Montreal, PQ, Canada

[14] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[15] Katholieke Univ Leuven Hosp, Dept Obstet & Gynaecol, Div Gynecol Oncol, Louvain, Belgium

[16] Katholieke Univ Leuven Hosp, Leuven Canc Inst, Louvain, Belgium

[17] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA

[18] Yale Univ, Sch Med, New Haven, CT USA

[19] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Ctr Nacl Genotipac, Madrid, Spain

[20] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[21] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA

[22] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Lebanon, NH USA

[23] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA

[24] Univ Kansas, Ctr Canc, Kansas IDeA Network Biomed Res Excellence Bioinfo, Kansas City, KS USA

[25] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[26] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[27] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA

[28] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England

[29] Mayo Clin, Dept Med Oncol, Rochester, MN USA

[30] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands

[31] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands

[32] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA

[33] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland

[34] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[35] Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, Louvain, Belgium

[36] VIB, VRC, Louvain, Belgium

[37] CESP Ctr Res Epidemiol & Populat Hlth, U1018, INSERM, Villejuif, France

[38] Univ Paris Sud, UMRS, Villejuif, France

[39] CNIO, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid, Spain

[40] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA

[41] Univ Sheffield, Dept Oncol, Canc Res UK Norkshire Canc Res Sheffield Canc Red, Sheffield, S Yorkshire, England

[42] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany

[43] DKFZ, Mol Epidemiol Grp, Heidelberg, Germany

[44] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany

[45] Univ Cologne, Primarmed Versorgung PMV Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany

[46] Kings Coll London, Div Canc Studies, Natl Inst Hlth Res NIHR, Comprehens Biomed Res Ctr,Guys & St Thomas Natl H, London WC2R 2LS, England

[47] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany

[48] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[49] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada

[50] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 04期

基金：

英国惠康基金; 加拿大健康研究院; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; REVERSE-TRANSCRIPTASE; SUSCEPTIBILITY LOCI; TERT-CLPTM1L LOCUS; GENETIC-VARIATION; COMMON VARIANTS; BUCCAL CELLS; FIBROBLASTS; SEQUENCE; POLYMORPHISM;

D O I：

10.1038/ng.2566

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：371 / 384

页数：14

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