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. Johnstonw; Juliet D. French; Xiaoqing Chen; Maren Weischer; Sune F. 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; Francis Bacot; Ignace Vergote; Sandrina Lambrechts; Evelyn Despierre; Harvey A. Risch; Anna Gonzalez-Neira; Mary Anne Rossing; Guillermo Pita; Jennifer A. Doherty; Nuria Alvarez; Melissa C. Larson; Brooke L. Fridley; Nils Schoof; Jan C. Oosterwijk; Australian Canc Study; Australian Ovarian Canc Study; Kathleen Cuningham Fdn Consortium; Gene Environm Interactimi Breast; Swedish Breast Canc Study SWE-BRCA; Hereditary Breast Ovarian Canc Res; Epidemiological Study BRCA1; Genetic Modifiers Canc Risk BRCA1

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. Johnstonw, Juliet D. French, Xiaoqing ChenMaren Weischer, Sune F. 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, Francis Bacot, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A. Risch, Anna Gonzalez-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A. Doherty, Nuria Alvarez, Melissa C. Larson, Brooke L. Fridley, Nils Schoof, Jan C. Oosterwijk, Australian Canc Study, Australian Ovarian Canc Study, Kathleen Cuningham Fdn Consortium, Gene Environm Interactimi Breast, Swedish Breast Canc Study SWE-BRCA, Hereditary Breast Ovarian Canc Res, Epidemiological Study BRCA1, Genetic Modifiers Canc Risk BRCA1

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Samenvatting

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.

Originele taal-2	English
Pagina's (van-tot)	371-384
Aantal pagina's	14
Tijdschrift	Nature Genetics
Volume	45
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1038/ng.2566
Status	Published - apr.-2013

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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., Johnstonw, R. L., French, J. D., ... Genetic Modifiers Canc Risk BRCA1 (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{1c0627b3df2f4415bb41290fcfc96d6c,

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 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.",

keywords = "GENOME-WIDE ASSOCIATION, REVERSE-TRANSCRIPTASE HTERT, SUSCEPTIBILITY LOCI, TERT-CLPTM1L LOCUS, GENETIC-VARIATION, COMMON VARIANTS, BUCCAL CELLS, FIBROBLASTS, CARCINOMA, METAANALYSIS",

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 Johnstonw, {Rebecca L.} and French, {Juliet D.} and Xiaoqing Chen and Maren Weischer and Nielsen, {Sune F.} 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 Francis Bacot and Ignace Vergote and Sandrina Lambrechts and Evelyn Despierre and Risch, {Harvey A.} and Anna Gonzalez-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 Oosterwijk, {Jan C.} and {Australian Canc Study} and {Australian Ovarian Canc Study} and {Kathleen Cuningham Fdn Consortium} and {Gene Environm Interactimi Breast} and {Swedish Breast Canc Study SWE-BRCA} and {Hereditary Breast Ovarian Canc Res} and {Epidemiological Study BRCA1} and {Genetic Modifiers Canc Risk BRCA1}",

year = "2013",

month = apr,

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, Johnstonw, 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, Gonzalez-Neira, A, Rossing, MA, Pita, G, Doherty, JA, Alvarez, N, Larson, MC, Fridley, BL, Schoof, N, Oosterwijk, JC, Australian Canc Study, Australian Ovarian Canc Study, Kathleen Cuningham Fdn Consortium, Gene Environm Interactimi Breast, Swedish Breast Canc Study SWE-BRCA, Hereditary Breast Ovarian Canc Res, Epidemiological Study BRCA1 & Genetic Modifiers Canc Risk BRCA1 2013, 'Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer', Nature Genetics, vol. 45, nr. 4, blz. 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 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 - Oosterwijk, Jan C.

AU - Australian Canc Study

AU - Australian Ovarian Canc Study

AU - Kathleen Cuningham Fdn Consortium

AU - Gene Environm Interactimi Breast

AU - Swedish Breast Canc Study SWE-BRCA

AU - Hereditary Breast Ovarian Canc Res

AU - Epidemiological Study BRCA1

AU - Genetic Modifiers Canc Risk BRCA1

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.

KW - GENOME-WIDE ASSOCIATION

KW - REVERSE-TRANSCRIPTASE HTERT

KW - SUSCEPTIBILITY LOCI

KW - TERT-CLPTM1L LOCUS

KW - GENETIC-VARIATION

KW - COMMON VARIANTS

KW - BUCCAL CELLS

KW - FIBROBLASTS

KW - CARCINOMA

KW - METAANALYSIS

U2 - 10.1038/ng.2566

DO - 10.1038/ng.2566

M3 - Article

SN - 1061-4036

VL - 45

SP - 371

EP - 384

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -