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

Stig E 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 Fallgaard Nielsen; Melanie J Maranian; Maya Ghoussaini; Shahana Ahmed; Caroline Baynes; Manjeet K Bolla; Qin Wang; Joe Dennis; Lesley McGuffog; Daniel Barrowdale; Andrew 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; Melissa C Larson; Brooke L Fridley; Nils Schoof; Nick Orr; Australian Cancer Study

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 E 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 Fallgaard Nielsen, Melanie J Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew 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, Melissa C Larson, Brooke L Fridley, Nils Schoof, Nick Orr, Australian Cancer Study

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

464 Citations (Scopus)

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.

Original language	English
Pages (from-to)	371-84, 384e1-2
Journal	Nature Genetics
Volume	45
Issue number	4
DOIs	https://doi.org/10.1038/ng.2566
Publication status	Published - Apr 2013

Keywords

Alternative Splicing
Biomarkers, Tumor
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
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.2566

Cite this

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 Cancer Study (2013). Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nature Genetics, 45(4), 371-84, 384e1-2. https://doi.org/10.1038/ng.2566

@article{0d07f2036b1c44b38e0a0275001ea1ac,

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, Biomarkers, Tumor, 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, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

author = "Bojesen, {Stig E} 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 Fallgaard} 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 Andrew Lee 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 Larson, {Melissa C} and Fridley, {Brooke L} and Nils Schoof and Nick Orr and {Australian Cancer Study}",

year = "2013",

month = apr,

doi = "10.1038/ng.2566",

language = "English",

volume = "45",

pages = "371--84, 384e1--2",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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, A, 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, Larson, MC, Fridley, BL, Schoof, N, Orr, N & Australian Cancer Study 2013, 'Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer', Nature Genetics, vol. 45, no. 4, pp. 371-84, 384e1-2. 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 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 Fallgaard

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, 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 - Larson, Melissa C

AU - Fridley, Brooke L

AU - Schoof, Nils

AU - Orr, Nick

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.

KW - Alternative Splicing

KW - Biomarkers, Tumor

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 - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1038/ng.2566

DO - 10.1038/ng.2566

M3 - Article

C2 - 23535731

SN - 1061-4036

VL - 45

SP - 371-84, 384e1-2

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

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this