Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

JD French; M Ghoussaini; SL Edwards; KB Meyer; K Michailidou; S (Shahana) Ahmed; Salima Khan; MJ Maranian; M O'Reilly; KM Hillman; JA Betts; T Carro; PJ Bailey; E Dicks; J Beesley; J Tyrer; AT Maia; A Beck; NW Knoblauch; Constance Chen; P Kraft; D Barnes; A Gonzalez-Neira; MR Alonso; D Herrero; DC Tessier; D Vincent; F Bacot; C Luccarini; C Baynes; D Conroy; J Dennis; MK Bolla; Q (Qing) Wang; JL Hopper; MC Southey; Marjanka K Schmidt; A Broeks; S Verhoef; S Cornelissen; K Muir; A Lophatananon; S Stewart-Brown; P Siriwanarangsan; PA Fasching; CR Loehberg; AB Ekici; MW Beckmann; J Peto; IDS Silva; N Johnson; Z Aitken; EJ Sawyer; I Tomlinson; MJ Kerin; N Miller; F Marme; A Schneeweiss; C Sohn; B Burwinkel; P Guenel; T Truong; P Laurent-Puig; F Menegaux; SE Bojesen; NG Nordestgaard; SF Nielsen; H Flyger; RL Milne; MP Zamora; JIA Perez; J Benitez; H Anton-Culver; H Brenner; H Muller; V Arndt; C Stegmaier; A Meind; P Lichtner; RK Schmutzler; C Engel; H Brauch; U Hamann; C Justenhoven; K Aaltonen; P Heikkila; K Aittomaki; C Blomqvist; K Matsuo; H Ito; H Iwata; A Sueta; NV Bogdanova; NN Antonenkova; T Dork; A Lindblom; S Margolin; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; AH Wu; CC Tseng; D van den Berg; DO Stram; D Lambrechts; S Peeters; A Smeets; G Floris; J Chang-Claude; A Rudolph; S Nickels; D Flesch-Janys; P Radice; P Peterlongo; B Bonanni; D Sardella; FJ Couch; XS Wang; VS Pankratz; A van der Lee; GG Giles; G Severi; L Baglietto; CA Haiman; BE Henderson; FR Schumacher; L Le Marchand; J Simard; MS Goldberg; F Labreche; M Dumont; SH Teo; CH Yip; CH Ng; EN Vithana; V Kristensen; W Zheng; S Deming-Halverson; M Shrubsole; JR Long; R Winqvist; K Pylkas; A Jukkola-Vuorinen; M Grip; IL Andrulis; JA Knight; G Glendon; AM Mulligan; P Devilee; Caroline Seynaeve; M Garcia-Closas; J Figueroa; SJ Chanock; J Lissowska; K Czene; D Klevebring; N Schoof; Maartje Hooning; John Martens; Margriet Collee; Madeleine Tilanus - Linthorst; P Hall; JM Li; JJ Liu; K Humphreys; XO Shu; W Lu; YT Gao; H Cai; A Cox; SP Balasubramanian; W Blot; LB Signorello; QY Cai; PDP Pharoah; CS Healey; M Shah; KA Pooley; D Kang; KY Yoo; DY Noh; M Hartman; H Miao; JH Sng; X Sim; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; S Sangrajrang; V Gaborieau; J Mckay; AE Toland; CB Ambrosone; D Yannoukakos; AK Godwin; CY Shen; CN Hsiung; PE Wu; ST Chen; A Swerdlow; A Ashworth; N Orr; MJ Schoemaker; BAJ Ponder; H Nevanlinna; MA Brown; G Chenevix-Trench; DF Easton; AM Dunning

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

JD French
, M Ghoussaini
, SL Edwards
, KB Meyer
, K Michailidou
, S (Shahana) Ahmed
, Salima Khan
, MJ Maranian
, M O'Reilly
, KM Hillman
, JA Betts
, T Carro
, PJ Bailey
, E Dicks
, J Beesley
, J Tyrer
, AT Maia
, A Beck
, NW Knoblauch
, Constance Chen

P Kraft, D Barnes, A Gonzalez-Neira, MR Alonso, D Herrero, DC Tessier, D Vincent, F Bacot, C Luccarini, C Baynes, D Conroy, J Dennis, MK Bolla, Q (Qing) Wang, JL Hopper, MC Southey, Marjanka K Schmidt, A Broeks, S Verhoef, S Cornelissen, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, PA Fasching, CR Loehberg, AB Ekici, MW Beckmann, J Peto, IDS Silva, N Johnson, Z Aitken, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, F Marme, A Schneeweiss, C Sohn, B Burwinkel, P Guenel, T Truong, P Laurent-Puig, F Menegaux, SE Bojesen, NG Nordestgaard, SF Nielsen, H Flyger, RL Milne, MP Zamora, JIA Perez, J Benitez, H Anton-Culver, H Brenner, H Muller, V Arndt, C Stegmaier, A Meind, P Lichtner, RK Schmutzler, C Engel, H Brauch, U Hamann, C Justenhoven, K Aaltonen, P Heikkila, K Aittomaki, C Blomqvist, K Matsuo, H Ito, H Iwata, A Sueta, NV Bogdanova, NN Antonenkova, T Dork, A Lindblom, S Margolin, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, AH Wu, CC Tseng, D van den Berg, DO Stram, D Lambrechts, S Peeters, A Smeets, G Floris, J Chang-Claude, A Rudolph, S Nickels, D Flesch-Janys, P Radice, P Peterlongo, B Bonanni, D Sardella, FJ Couch, XS Wang, VS Pankratz, A van der Lee, GG Giles, G Severi, L Baglietto, CA Haiman, BE Henderson, FR Schumacher, L Le Marchand, J Simard, MS Goldberg, F Labreche, M Dumont, SH Teo, CH Yip, CH Ng, EN Vithana, V Kristensen, W Zheng, S Deming-Halverson, M Shrubsole, JR Long, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, IL Andrulis, JA Knight, G Glendon, AM Mulligan, P Devilee, Caroline Seynaeve, M Garcia-Closas, J Figueroa, SJ Chanock, J Lissowska, K Czene, D Klevebring, N Schoof, Maartje Hooning, John Martens, Margriet Collee, Madeleine Tilanus - Linthorst, P Hall, JM Li, JJ Liu, K Humphreys, XO Shu, W Lu, YT Gao, H Cai, A Cox, SP Balasubramanian, W Blot, LB Signorello, QY Cai, PDP Pharoah, CS Healey, M Shah, KA Pooley, D Kang, KY Yoo, DY Noh, M Hartman, H Miao, JH Sng, X Sim, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, S Sangrajrang, V Gaborieau, J Mckay, AE Toland, CB Ambrosone, D Yannoukakos, AK Godwin, CY Shen, CN Hsiung, PE Wu, ST Chen, A Swerdlow, A Ashworth, N Orr, MJ Schoemaker, BAJ Ponder, H Nevanlinna, MA Brown, G Chenevix-Trench, DF Easton, AM Dunning

External organisation

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

177 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
Pages (from-to)	489-503
Number of pages	15
Journal	American Journal of Human Genetics
Volume	92
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2013.01.002
Publication status	Published - 2013

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

SDG 3 Good Health and Well-being

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EMC MM-03-47-11
EMC MM-03-86-01

Access to Document

10.1016/j.ajhg.2013.01.002

http://hdl.handle.net/1765/58933

Cite this

French, JD., Ghoussaini, M., Edwards, SL., Meyer, KB., Michailidou, K., Ahmed, S., Khan, S., Maranian, MJ., O'Reilly, M., Hillman, KM., Betts, JA., Carro, T., Bailey, PJ., Dicks, E., Beesley, J., Tyrer, J., Maia, AT., Beck, A., Knoblauch, NW., ... Dunning, AM. (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

@article{f88d232f05dc4529b1823ac06a4d7e5d,

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 = "JD French and M Ghoussaini and SL Edwards and KB Meyer and K Michailidou and Ahmed, \{S (Shahana)\} and Salima Khan and MJ Maranian and M O'Reilly and KM Hillman and JA Betts and T Carro and PJ Bailey and E Dicks and J Beesley and J Tyrer and AT Maia and A Beck and NW Knoblauch and Constance Chen and P Kraft and D Barnes and A Gonzalez-Neira and MR Alonso and D Herrero and DC Tessier and D Vincent and F Bacot and C Luccarini and C Baynes and D Conroy and J Dennis and MK Bolla and Wang, \{Q (Qing)\} and JL Hopper and MC Southey and Schmidt, \{Marjanka K\} and A Broeks and S Verhoef and S Cornelissen and K Muir and A Lophatananon and S Stewart-Brown and P Siriwanarangsan and PA Fasching and CR Loehberg and AB Ekici and MW Beckmann and J Peto and IDS Silva and N Johnson and Z Aitken and EJ Sawyer and I Tomlinson and MJ Kerin and N Miller and F Marme and A Schneeweiss and C Sohn and B Burwinkel and P Guenel and T Truong and P Laurent-Puig and F Menegaux and SE Bojesen and NG Nordestgaard and SF Nielsen and H Flyger and RL Milne and MP Zamora and JIA Perez and J Benitez and H Anton-Culver and H Brenner and H Muller and V Arndt and C Stegmaier and A Meind and P Lichtner and RK Schmutzler and C Engel and H Brauch and U Hamann and C Justenhoven and K Aaltonen and P Heikkila and K Aittomaki and C Blomqvist and K Matsuo and H Ito and H Iwata and A Sueta and NV Bogdanova and NN Antonenkova and T Dork and A Lindblom and S Margolin and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and AH Wu and CC Tseng and \{van den Berg\}, D and DO Stram and D Lambrechts and S Peeters and A Smeets and G Floris and J Chang-Claude and A Rudolph and S Nickels and D Flesch-Janys and P Radice and P Peterlongo and B Bonanni and D Sardella and FJ Couch and XS Wang and VS Pankratz and \{van der Lee\}, A and GG Giles and G Severi and L Baglietto and CA Haiman and BE Henderson and FR Schumacher and \{Le Marchand\}, L and J Simard and MS Goldberg and F Labreche and M Dumont and SH Teo and CH Yip and CH Ng and EN Vithana and V Kristensen and W Zheng and S Deming-Halverson and M Shrubsole and JR Long and R Winqvist and K Pylkas and A Jukkola-Vuorinen and M Grip and IL Andrulis and JA Knight and G Glendon and AM Mulligan and P Devilee and Caroline Seynaeve and M Garcia-Closas and J Figueroa and SJ Chanock and J Lissowska and K Czene and D Klevebring and N Schoof and Maartje Hooning and John Martens and Margriet Collee and \{Tilanus - Linthorst\}, Madeleine and P Hall and JM Li and JJ Liu and K Humphreys and XO Shu and W Lu and YT Gao and H Cai and A Cox and SP Balasubramanian and W Blot and LB Signorello and QY Cai and PDP Pharoah and CS Healey and M Shah and KA Pooley and D Kang and KY Yoo and DY Noh and M Hartman and H Miao and JH Sng and X Sim and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and S Sangrajrang and V Gaborieau and J Mckay and AE Toland and CB Ambrosone and D Yannoukakos and AK Godwin and CY Shen and CN Hsiung and PE Wu and ST Chen and A Swerdlow and A Ashworth and N Orr and MJ Schoemaker and BAJ Ponder and H Nevanlinna and MA Brown and G Chenevix-Trench and DF Easton and AM Dunning",

year = "2013",

doi = "10.1016/j.ajhg.2013.01.002",

language = "English",

volume = "92",

pages = "489--503",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

French, JD, Ghoussaini, M, Edwards, SL, Meyer, KB, Michailidou, K, Ahmed, S, Khan, S, Maranian, MJ, O'Reilly, M, Hillman, KM, Betts, JA, Carro, T, Bailey, PJ, Dicks, E, Beesley, J, Tyrer, J, Maia, AT, Beck, A, Knoblauch, NW, Chen, C, Kraft, P, Barnes, D, Gonzalez-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, Silva, IDS, Johnson, N, Aitken, Z, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Laurent-Puig, P, Menegaux, F, Bojesen, SE, Nordestgaard, NG, Nielsen, SF, Flyger, H, Milne, RL, Zamora, MP, Perez, JIA, Benitez, J, Anton-Culver, H, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Meind, A, Lichtner, P, Schmutzler, RK, Engel, C, Brauch, H, Hamann, U, Justenhoven, C, Aaltonen, K, Heikkila, P, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Sueta, A, Bogdanova, NV, Antonenkova, NN, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Peeters, S, Smeets, A, Floris, G, Chang-Claude, J, Rudolph, A, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Sardella, D, Couch, FJ, Wang, XS, Pankratz, VS, van der Lee, A, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, FR, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, Ng, CH, Vithana, EN, Kristensen, V, Zheng, W, Deming-Halverson, S, Shrubsole, M, Long, JR, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devilee, P, Seynaeve, C, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Schoof, N, Hooning, M , Martens, J , Collee, M , Tilanus - Linthorst, M, Hall, P, Li, JM, Liu, JJ, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Balasubramanian, SP, Blot, W, Signorello, LB, Cai, QY, Pharoah, PDP, Healey, CS, Shah, M, Pooley, KA, Kang, D, Yoo, KY, Noh, DY, Hartman, M, Miao, H, Sng, JH, Sim, X, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Mckay, J, Toland, AE, Ambrosone, CB, Yannoukakos, D, Godwin, AK, Shen, CY, Hsiung, CN, Wu, PE, Chen, ST, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Ponder, BAJ, Nevanlinna, H, Brown, MA, Chenevix-Trench, G, Easton, DF & Dunning, AM 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

TY - JOUR

T1 - Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

AU - French, JD

AU - Ghoussaini, M

AU - Edwards, SL

AU - Meyer, KB

AU - Michailidou, K

AU - Ahmed, S (Shahana)

AU - Khan, Salima

AU - Maranian, MJ

AU - O'Reilly, M

AU - Hillman, KM

AU - Betts, JA

AU - Carro, T

AU - Bailey, PJ

AU - Dicks, E

AU - Beesley, J

AU - Tyrer, J

AU - Maia, AT

AU - Beck, A

AU - Knoblauch, NW

AU - Chen, Constance

AU - Kraft, P

AU - Barnes, D

AU - Gonzalez-Neira, A

AU - Alonso, MR

AU - Herrero, D

AU - Tessier, DC

AU - Vincent, D

AU - Bacot, F

AU - Luccarini, C

AU - Baynes, C

AU - Conroy, D

AU - Dennis, J

AU - Bolla, MK

AU - Wang, Q (Qing)

AU - Hopper, JL

AU - Southey, MC

AU - Schmidt, Marjanka K

AU - Broeks, A

AU - Verhoef, S

AU - Cornelissen, S

AU - Muir, K

AU - Lophatananon, A

AU - Stewart-Brown, S

AU - Siriwanarangsan, P

AU - Fasching, PA

AU - Loehberg, CR

AU - Ekici, AB

AU - Beckmann, MW

AU - Peto, J

AU - Silva, IDS

AU - Johnson, N

AU - Aitken, Z

AU - Sawyer, EJ

AU - Tomlinson, I

AU - Kerin, MJ

AU - Miller, N

AU - Marme, F

AU - Schneeweiss, A

AU - Sohn, C

AU - Burwinkel, B

AU - Guenel, P

AU - Truong, T

AU - Laurent-Puig, P

AU - Menegaux, F

AU - Bojesen, SE

AU - Nordestgaard, NG

AU - Nielsen, SF

AU - Flyger, H

AU - Milne, RL

AU - Zamora, MP

AU - Perez, JIA

AU - Benitez, J

AU - Anton-Culver, H

AU - Brenner, H

AU - Muller, H

AU - Arndt, V

AU - Stegmaier, C

AU - Meind, A

AU - Lichtner, P

AU - Schmutzler, RK

AU - Engel, C

AU - Brauch, H

AU - Hamann, U

AU - Justenhoven, C

AU - Aaltonen, K

AU - Heikkila, P

AU - Aittomaki, K

AU - Blomqvist, C

AU - Matsuo, K

AU - Ito, H

AU - Iwata, H

AU - Sueta, A

AU - Bogdanova, NV

AU - Antonenkova, NN

AU - Dork, T

AU - Lindblom, A

AU - Margolin, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Wu, AH

AU - Tseng, CC

AU - van den Berg, D

AU - Stram, DO

AU - Lambrechts, D

AU - Peeters, S

AU - Smeets, A

AU - Floris, G

AU - Chang-Claude, J

AU - Rudolph, A

AU - Nickels, S

AU - Flesch-Janys, D

AU - Radice, P

AU - Peterlongo, P

AU - Bonanni, B

AU - Sardella, D

AU - Couch, FJ

AU - Wang, XS

AU - Pankratz, VS

AU - van der Lee, A

AU - Giles, GG

AU - Severi, G

AU - Baglietto, L

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, FR

AU - Le Marchand, L

AU - Simard, J

AU - Goldberg, MS

AU - Labreche, F

AU - Dumont, M

AU - Teo, SH

AU - Yip, CH

AU - Ng, CH

AU - Vithana, EN

AU - Kristensen, V

AU - Zheng, W

AU - Deming-Halverson, S

AU - Shrubsole, M

AU - Long, JR

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Mulligan, AM

AU - Devilee, P

AU - Seynaeve, Caroline

AU - Garcia-Closas, M

AU - Figueroa, J

AU - Chanock, SJ

AU - Lissowska, J

AU - Czene, K

AU - Klevebring, D

AU - Schoof, N

AU - Hooning, Maartje

AU - Martens, John

AU - Collee, Margriet

AU - Tilanus - Linthorst, Madeleine

AU - Hall, P

AU - Li, JM

AU - Liu, JJ

AU - Humphreys, K

AU - Shu, XO

AU - Lu, W

AU - Gao, YT

AU - Cai, H

AU - Cox, A

AU - Balasubramanian, SP

AU - Blot, W

AU - Signorello, LB

AU - Cai, QY

AU - Pharoah, PDP

AU - Healey, CS

AU - Shah, M

AU - Pooley, KA

AU - Kang, D

AU - Yoo, KY

AU - Noh, DY

AU - Hartman, M

AU - Miao, H

AU - Sng, JH

AU - Sim, X

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Sangrajrang, S

AU - Gaborieau, V

AU - Mckay, J

AU - Toland, AE

AU - Ambrosone, CB

AU - Yannoukakos, D

AU - Godwin, AK

AU - Shen, CY

AU - Hsiung, CN

AU - Wu, PE

AU - Chen, ST

AU - Swerdlow, A

AU - Ashworth, A

AU - Orr, N

AU - Schoemaker, MJ

AU - Ponder, BAJ

AU - Nevanlinna, H

AU - Brown, MA

AU - Chenevix-Trench, G

AU - Easton, DF

AU - Dunning, AM

PY - 2013

Y1 - 2013

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 - 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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