Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

Juliet D French; Maya Ghoussaini; Stacey L Edwards; Kerstin B Meyer; Kyriaki Michailidou; Shahana Ahmed; Sofia Khan; Mel J Maranian; Martin O'Reilly; Kristine M Hillman; Joshua A Betts; Thomas Carroll; Peter J Bailey; Ed Dicks; Jonathan Beesley; Jonathan Tyrer; Ana-Teresa Maia; Andrew Beck; Nicholas W Knoblauch; Constance Chen; Peter Kraft; Daniel Barnes; Anna González-Neira; M Rosario Alonso; Daniel Herrero; Daniel C Tessier; Daniel Vincent; Francois Bacot; Craig Luccarini; Caroline Baynes; Don Conroy; Joe Dennis; Manjeet K Bolla; Qin Wang; John L Hopper; Melissa C Southey; Marjanka K Schmidt; Annegien Broeks; Senno Verhoef; Sten Cornelissen; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Peter A Fasching; Christian R Loehberg; Arif B Ekici; Matthias W Beckmann; Julian Peto; Børge G Nordestgaard; GENICA Network

doi:10.1016/j.ajhg.2013.01.002

Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

Juliet D French, Maya Ghoussaini, Stacey L Edwards, Kerstin B Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J Maranian, Martin O'Reilly, Kristine M Hillman, Joshua A Betts, Thomas Carroll, Peter J Bailey, Ed Dicks, Jonathan Beesley, Jonathan Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas W Knoblauch, Constance ChenPeter Kraft, Daniel Barnes, Anna González-Neira, M Rosario Alonso, Daniel Herrero, Daniel C Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K Bolla, Qin Wang, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Christian R Loehberg, Arif B Ekici, Matthias W Beckmann, Julian Peto, Børge G Nordestgaard, GENICA Network

145 Citations (Scopus)

Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Original language	English
Journal	American Journal of Human Genetics
Volume	92
Issue number	4
Pages (from-to)	489-503
Number of pages	15
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2013.01.002
Publication status	Published - 4 Apr 2013

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French, J. D., Ghoussaini, M., Edwards, S. L., Meyer, K. B., Michailidou, K., Ahmed, S., Khan, S., Maranian, M. J., O'Reilly, M., Hillman, K. M., Betts, J. A., Carroll, T., Bailey, P. J., Dicks, E., Beesley, J., Tyrer, J., Maia, A-T., Beck, A., Knoblauch, N. W., ... GENICA Network (2013). Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. American Journal of Human Genetics, 92(4), 489-503. https://doi.org/10.1016/j.ajhg.2013.01.002

French, JD, Ghoussaini, M, Edwards, SL, Meyer, KB, Michailidou, K, Ahmed, S, Khan, S, Maranian, MJ, O'Reilly, M, Hillman, KM, Betts, JA, Carroll, T, Bailey, PJ, Dicks, E, Beesley, J, Tyrer, J, Maia, A-T, Beck, A, Knoblauch, NW, Chen, C, Kraft, P, Barnes, D, González-Neira, A, Alonso, MR, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Conroy, D, Dennis, J, Bolla, MK, Wang, Q, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Loehberg, CR, Ekici, AB, Beckmann, MW, Peto, J, Nordestgaard, BG & GENICA Network 2013, 'Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers', American Journal of Human Genetics, vol. 92, no. 4, pp. 489-503. https://doi.org/10.1016/j.ajhg.2013.01.002

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title = "Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers",

abstract = "Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.",

author = "French, {Juliet D} and Maya Ghoussaini and Edwards, {Stacey L} and Meyer, {Kerstin B} and Kyriaki Michailidou and Shahana Ahmed and Sofia Khan and Maranian, {Mel J} and Martin O'Reilly and Hillman, {Kristine M} and Betts, {Joshua A} and Thomas Carroll and Bailey, {Peter J} and Ed Dicks and Jonathan Beesley and Jonathan Tyrer and Ana-Teresa Maia and Andrew Beck and Knoblauch, {Nicholas W} and Constance Chen and Peter Kraft and Daniel Barnes and Anna Gonz{\'a}lez-Neira and Alonso, {M Rosario} and Daniel Herrero and Tessier, {Daniel C} and Daniel Vincent and Francois Bacot and Craig Luccarini and Caroline Baynes and Don Conroy and Joe Dennis and Bolla, {Manjeet K} and Qin Wang and Hopper, {John L} and Southey, {Melissa C} and Schmidt, {Marjanka K} and Annegien Broeks and Senno Verhoef and Sten Cornelissen and Kenneth Muir and Artitaya Lophatananon and Sarah Stewart-Brown and Pornthep Siriwanarangsan and Fasching, {Peter A} and Loehberg, {Christian R} and Ekici, {Arif B} and Beckmann, {Matthias W} and Julian Peto and Nordestgaard, {B{\o}rge G} and B{\o}rge Nordestgaard",

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T1 - Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

AU - French, Juliet D

AU - Ghoussaini, Maya

AU - Edwards, Stacey L

AU - Meyer, Kerstin B

AU - Michailidou, Kyriaki

AU - Ahmed, Shahana

AU - Khan, Sofia

AU - Maranian, Mel J

AU - O'Reilly, Martin

AU - Hillman, Kristine M

AU - Betts, Joshua A

AU - Carroll, Thomas

AU - Bailey, Peter J

AU - Dicks, Ed

AU - Beesley, Jonathan

AU - Tyrer, Jonathan

AU - Maia, Ana-Teresa

AU - Beck, Andrew

AU - Knoblauch, Nicholas W

AU - Chen, Constance

AU - Kraft, Peter

AU - Barnes, Daniel

AU - González-Neira, Anna

AU - Alonso, M Rosario

AU - Herrero, Daniel

AU - Tessier, Daniel C

AU - Vincent, Daniel

AU - Bacot, Francois

AU - Luccarini, Craig

AU - Baynes, Caroline

AU - Conroy, Don

AU - Dennis, Joe

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Hopper, John L

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Verhoef, Senno

AU - Cornelissen, Sten

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Fasching, Peter A

AU - Loehberg, Christian R

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - Nordestgaard, Børge G

AU - GENICA Network

PY - 2013/4/4

Y1 - 2013/4/4

N2 - Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

AB - Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

U2 - 10.1016/j.ajhg.2013.01.002

DO - 10.1016/j.ajhg.2013.01.002

M3 - Journal article

C2 - 23540573

SN - 0002-9297

VL - 92

SP - 489

EP - 503

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

Abstract

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