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

Stig Egil Bojesen; Karen A Pooley; Sharon E Johnatty; Jonathan Beesley; Kyriaki Michailidou; Jonathan P Tyrer; Stacey L Edwards; Hilda A Pickett; Howard C Shen; Chanel E Smart; Kristine M Hillman; Phuong L Mai; Kate Lawrenson; Michael D Stutz; Yi Lu; Rod Karevan; Nicholas Woods; Rebecca L Johnston; Juliet D French; Xiaoqing Chen; Maren Weischer; Sune Fuglsang Nielsen; Melanie J Maranian; Maya Ghoussaini; Shahana Ahmed; Caroline Baynes; Manjeet K Bolla; Qin Wang; Joe Dennis; Lesley McGuffog; Daniel Barrowdale; Andrew Roger Lee; Sue Healey; Michael Lush; Daniel C Tessier; Daniel Vincent; Françis Bacot; Ignace Vergote; Sandrina Lambrechts; Evelyn Despierre; Harvey A Risch; Anna González-Neira; Mary Anne Rossing; Guillermo Pita; Jennifer A Doherty; Nuria Alvarez; Mads Thomassen; Anne Bine Skytte; Torben A Kruse; Anne-Marie Gerdes; Australian Ovarian Cancer Study Group

doi:10.1038/ng.2566

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

Stig Egil Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, Kristine M Hillman, Phuong L Mai, Kate Lawrenson, Michael D Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L Johnston, Juliet D French, Xiaoqing ChenMaren Weischer, Sune Fuglsang Nielsen, Melanie J Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Roger Lee, Sue Healey, Michael Lush, Daniel C Tessier, Daniel Vincent, Françis Bacot, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A Doherty, Nuria Alvarez, Mads Thomassen, Anne Bine Skytte, Torben A Kruse, Anne-Marie Gerdes, Australian Ovarian Cancer Study Group

Københavns Universitet

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	45
Udgave nummer	4
Sider (fra-til)	371-384
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.2566
Status	Udgivet - 2013

Dokumenter og links

10.1038/ng.2566

Citationsformater

Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., Edwards, S. L., Pickett, H. A., Shen, H. C., Smart, C. E., Hillman, K. M., Mai, P. L., Lawrenson, K., Stutz, M. D., Lu, Y., Karevan, R., Woods, N., Johnston, R. L., French, J. D., ... Australian Ovarian Cancer Study Group (2013). Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nature Genetics, 45(4), 371-384. https://doi.org/10.1038/ng.2566

@article{1ef03f10297c4d06802c547396ac3be8,

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

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.",

keywords = "Alternative 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, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Telomerase, Telomere, Tumor Markers, Biological",

author = "Bojesen, {Stig Egil} and Pooley, {Karen A} and Johnatty, {Sharon E} and Jonathan Beesley and Kyriaki Michailidou and Tyrer, {Jonathan P} and Edwards, {Stacey L} and Pickett, {Hilda A} and Shen, {Howard C} and Smart, {Chanel E} and Hillman, {Kristine M} and Mai, {Phuong L} and Kate Lawrenson and Stutz, {Michael D} and Yi Lu and Rod Karevan and Nicholas Woods and Johnston, {Rebecca L} and French, {Juliet D} and Xiaoqing Chen and Maren Weischer and Nielsen, {Sune Fuglsang} and Maranian, {Melanie J} and Maya Ghoussaini and Shahana Ahmed and Caroline Baynes and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Lesley McGuffog and Daniel Barrowdale and Lee, {Andrew Roger} and Sue Healey and Michael Lush and Tessier, {Daniel C} and Daniel Vincent and Fran{\c c}is Bacot and Ignace Vergote and Sandrina Lambrechts and Evelyn Despierre and Risch, {Harvey A} and Anna Gonz{\'a}lez-Neira and Rossing, {Mary Anne} and Guillermo Pita and Doherty, {Jennifer A} and Nuria Alvarez and Mads Thomassen and Skytte, {Anne Bine} and Kruse, {Torben A} and Anne-Marie Gerdes and {Australian Ovarian Cancer Study Group}",

year = "2013",

doi = "10.1038/ng.2566",

language = "English",

volume = "45",

pages = "371--384",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

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, AR, Healey, S, Lush, M, Tessier, DC, Vincent, D, Bacot, F, Vergote, I, Lambrechts, S, Despierre, E, Risch, HA, González-Neira, A, Rossing, MA, Pita, G, Doherty, JA, Alvarez, N, Thomassen, M, Skytte, AB, Kruse, TA, Gerdes, A-M & Australian Ovarian Cancer Study Group 2013, 'Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer', Nature Genetics, bind 45, nr. 4, s. 371-384. https://doi.org/10.1038/ng.2566

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 Egil

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 Fuglsang

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 - Thomassen, Mads

AU - Skytte, Anne Bine

AU - Kruse, Torben A

AU - Gerdes, Anne-Marie

AU - Australian Ovarian Cancer Study Group

PY - 2013

Y1 - 2013

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.

KW - Alternative Splicing

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Chromatin

KW - DNA Methylation

KW - Female

KW - Gene Expression Profiling

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Luciferases

KW - Oligonucleotide Array Sequence Analysis

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Risk Factors

KW - Telomerase

KW - Telomere

KW - Tumor Markers, Biological

U2 - 10.1038/ng.2566

DO - 10.1038/ng.2566

M3 - Journal article

C2 - 23535731

SN - 1061-4036

VL - 45

SP - 371

EP - 384

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

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Citationsformater