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 F 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; Børge G Nordestgaard; Svend Aage Engelholm; Claus K Høgdall; Anne-Marie Gerdes; 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 F 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, Børge G Nordestgaard, Svend Aage Engelholm, Claus K Høgdall, Anne-Marie Gerdes, Australian Cancer Study

393 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
Journal	Nature Genetics
Volume	45
Issue number	4
Pages (from-to)	371-84, 384e1-2
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2566
Publication 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., 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

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, Nordestgaard, BG, Engelholm, SA, Høgdall, CK , Gerdes, A-M & 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

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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.",

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 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 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 Nordestgaard, {B{\o}rge G} and Engelholm, {Svend Aage} and H{\o}gdall, {Claus K} and Anne-Marie Gerdes and B{\o}rge Nordestgaard",

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doi = "10.1038/ng.2566",

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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

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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

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SN - 1061-4036

VL - 45

SP - 371-84, 384e1-2

JO - Nature: New biology

JF - Nature: New biology

IS - 4

ER -

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

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