An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Asaf Wyszynski; Chi-chen Hong; Kristin Lam; Kyriaki Michailidou; Christian Lytle; Song Yao; Yali Zhang; Manjeet K Bolla; Qin Wang; Joe Dennis; John L Hopper; Melissa C Southey; Marjanka K Schmidt; Annegien Broeks; Kenneth Muir; Artitaya Lophatananon; Peter A Fasching; Matthias W Beckmann; Julian Peto; Isabel dos Santos Silva; Elinor J Sawyer; Ian Tomlinson; Barbara Burwinkel; Frederik Marme; Pascal Guénel; Therese Truong; Stig E. Bojesen; Børge G. Nordestgaard; Anna González-Neira; Javier Benitez; Susan L Neuhausen; Hermann Brenner; Aida Karina Dieffenbach; Alfons Meindl; Rita K Schmutzler; Hiltrud Brauch; Heli Nevanlinna; Sofia Khan; Keitaro Matsuo; Hidemi Ito; Thilo Doerk; Natalia V Bogdanova; Annika Lindblom; Sara Margolin; Arto Mannermaa; Veli-Matti Kosma; Anna H Wu; David Van Den Berg; Diether Lambrechts; Hans Wildiers; Jenny Chang-Claude; Anja Rudolph; Paolo Radice; Paolo Peterlongo; Fergus J Couch; Janet E Olson; Graham Giles; Roger L Milne; Christopher A Haiman; Brian E Henderson; Martine Dumont; Soo-Hwang Teo; Tien Y Wong; Vessela Kristensen; Wei Zheng; Jirong Long; Robert Winqvist; Katri Pylkäs; Irene L Andrulis; Julia A Knight; Peter Devilee; Caroline Seynaeve; Montserrat García-Closas; Jonine Figueroa; Daniel Klevebring; Kamila Czene; Maartje J Hooning; Ans M W van den Ouweland; Hatef Darabi; Xiao-Ou Shu; Yu-Tang Gao; Angela Cox; William Blot; Lisa B Signorello; Mitul Shah; Daehee Kang; Ji-Yeob Choi; Mikael Hartman; Hui Miao; Ute Hamann; Anna Jakubowska; Jan Lubinski; Suleeporn Sangrajrang; James McKay; Amanda E Toland; Drakoulis Yannoukakos; Chen-Yang Shen; Pei-Ei Wu; Anthony Swerdlow; Nick Orr; Jacques Simard; Paul P D Pharoah; Alison M Dunning; Georgia Chenevix-Trench; Per Hall; Elisa V Bandera; Chris Amos; Christine B Ambrosone; Douglas F Easton; Michael D. Cole

doi:10.1093/hmg/ddw223

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Asaf Wyszynski, Chi-chen Hong, Kristin Lam, Kyriaki Michailidou, Christian Lytle, Song Yao, Yali Zhang, Manjeet K Bolla, Qin Wang, Joe Dennis, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Julian Peto, Isabel dos Santos SilvaElinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Therese Truong, Stig E. Bojesen, Børge G. Nordestgaard, Anna González-Neira, Javier Benitez, Susan L Neuhausen, Hermann Brenner, Aida Karina Dieffenbach, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Thilo Doerk, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Anna H Wu, David Van Den Berg, Diether Lambrechts, Hans Wildiers, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Fergus J Couch, Janet E Olson, Graham Giles, Roger L Milne, Christopher A Haiman, Brian E Henderson, Martine Dumont, Soo-Hwang Teo, Tien Y Wong, Vessela Kristensen, Wei Zheng, Jirong Long, Robert Winqvist, Katri Pylkäs, Irene L Andrulis, Julia A Knight, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Jonine Figueroa, Daniel Klevebring, Kamila Czene, Maartje J Hooning, Ans M W van den Ouweland, Hatef Darabi, Xiao-Ou Shu, Yu-Tang Gao, Angela Cox, William Blot, Lisa B Signorello, Mitul Shah, Daehee Kang, Ji-Yeob Choi, Mikael Hartman, Hui Miao, Ute Hamann, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, James McKay, Amanda E Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Pei-Ei Wu, Anthony Swerdlow, Nick Orr, Jacques Simard, Paul P D Pharoah, Alison M Dunning, Georgia Chenevix-Trench, Per Hall, Elisa V Bandera, Chris Amos, Christine B Ambrosone, Douglas F Easton, Michael D. Cole

Department of Clinical Medicine

18 Citations (Scopus)

Abstract

Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10^-19) and identify 13 additional linked variants (r² > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10^-15 - 5.6×10^-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

Original language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	17
Pages (from-to)	3863-3876
Number of pages	14
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw223
Publication status	Published - 1 Sept 2016

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Wyszynski, A., Hong, C., Lam, K., Michailidou, K., Lytle, C., Yao, S., Zhang, Y., Bolla, M. K., Wang, Q., Dennis, J., Hopper, J. L., Southey, M. C., Schmidt, M. K., Broeks, A., Muir, K., Lophatananon, A., Fasching, P. A., Beckmann, M. W., Peto, J., ... Cole, M. D. (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Human Molecular Genetics, 25(17), 3863-3876. https://doi.org/10.1093/hmg/ddw223

Wyszynski, A, Hong, C, Lam, K, Michailidou, K, Lytle, C, Yao, S, Zhang, Y, Bolla, MK, Wang, Q, Dennis, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Peto, J, dos Santos Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE , Nordestgaard, BG, González-Neira, A, Benitez, J, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Meindl, A, Schmutzler, RK, Brauch, H, Nevanlinna, H, Khan, S, Matsuo, K, Ito, H, Doerk, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Wu, AH, Van Den Berg, D, Lambrechts, D, Wildiers, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Couch, FJ, Olson, JE, Giles, G, Milne, RL, Haiman, CA, Henderson, BE, Dumont, M, Teo, S-H, Wong, TY, Kristensen, V, Zheng, W, Long, J, Winqvist, R, Pylkäs, K, Andrulis, IL, Knight, JA, Devilee, P, Seynaeve, C, García-Closas, M, Figueroa, J, Klevebring, D, Czene, K, Hooning, MJ, van den Ouweland, AMW, Darabi, H, Shu, X-O, Gao, Y-T, Cox, A, Blot, W, Signorello, LB, Shah, M, Kang, D, Choi, J-Y, Hartman, M, Miao, H, Hamann, U, Jakubowska, A, Lubinski, J, Sangrajrang, S, McKay, J, Toland, AE, Yannoukakos, D, Shen, C-Y, Wu, P-E, Swerdlow, A, Orr, N, Simard, J, Pharoah, PPD, Dunning, AM, Chenevix-Trench, G, Hall, P, Bandera, EV, Amos, C, Ambrosone, CB, Easton, DF & Cole, MD 2016, 'An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression', Human Molecular Genetics, vol. 25, no. 17, pp. 3863-3876. https://doi.org/10.1093/hmg/ddw223

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title = "An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression",

abstract = "Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.",

author = "Asaf Wyszynski and Chi-chen Hong and Kristin Lam and Kyriaki Michailidou and Christian Lytle and Song Yao and Yali Zhang and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Hopper, {John L} and Southey, {Melissa C} and Schmidt, {Marjanka K} and Annegien Broeks and Kenneth Muir and Artitaya Lophatananon and Fasching, {Peter A} and Beckmann, {Matthias W} and Julian Peto and {dos Santos Silva}, Isabel and Sawyer, {Elinor J} and Ian Tomlinson and Barbara Burwinkel and Frederik Marme and Pascal Gu{\'e}nel and Therese Truong and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Anna Gonz{\'a}lez-Neira and Javier Benitez and Neuhausen, {Susan L} and Hermann Brenner and Dieffenbach, {Aida Karina} and Alfons Meindl and Schmutzler, {Rita K} and Hiltrud Brauch and Heli Nevanlinna and Sofia Khan and Keitaro Matsuo and Hidemi Ito and Thilo Doerk and Bogdanova, {Natalia V} and Annika Lindblom and Sara Margolin and Arto Mannermaa and Veli-Matti Kosma and Wu, {Anna H} and {Van Den Berg}, David and Diether Lambrechts and Hans Wildiers and Jenny Chang-Claude and Anja Rudolph and Paolo Radice and Paolo Peterlongo and Couch, {Fergus J} and Olson, {Janet E} and Graham Giles and Milne, {Roger L} and Haiman, {Christopher A} and Henderson, {Brian E} and Martine Dumont and Soo-Hwang Teo and Wong, {Tien Y} and Vessela Kristensen and Wei Zheng and Jirong Long and Robert Winqvist and Katri Pylk{\"a}s and Andrulis, {Irene L} and Knight, {Julia A} and Peter Devilee and Caroline Seynaeve and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Daniel Klevebring and Kamila Czene and Hooning, {Maartje J} and {van den Ouweland}, {Ans M W} and Hatef Darabi and Xiao-Ou Shu and Yu-Tang Gao and Angela Cox and William Blot and Signorello, {Lisa B} and Mitul Shah and Daehee Kang and Ji-Yeob Choi and Mikael Hartman and Hui Miao and Ute Hamann and Anna Jakubowska and Jan Lubinski and Suleeporn Sangrajrang and James McKay and Toland, {Amanda E} and Drakoulis Yannoukakos and Chen-Yang Shen and Pei-Ei Wu and Anthony Swerdlow and Nick Orr and Jacques Simard and Pharoah, {Paul P D} and Dunning, {Alison M} and Georgia Chenevix-Trench and Per Hall and Bandera, {Elisa V} and Chris Amos and Ambrosone, {Christine B} and Easton, {Douglas F} and Cole, {Michael D.}",

year = "2016",

month = sep,

day = "1",

doi = "10.1093/hmg/ddw223",

language = "English",

volume = "25",

pages = "3863--3876",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

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TY - JOUR

T1 - An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

AU - Wyszynski, Asaf

AU - Hong, Chi-chen

AU - Lam, Kristin

AU - Michailidou, Kyriaki

AU - Lytle, Christian

AU - Yao, Song

AU - Zhang, Yali

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Hopper, John L

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - dos Santos Silva, Isabel

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Guénel, Pascal

AU - Truong, Therese

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - González-Neira, Anna

AU - Benitez, Javier

AU - Neuhausen, Susan L

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Brauch, Hiltrud

AU - Nevanlinna, Heli

AU - Khan, Sofia

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Doerk, Thilo

AU - Bogdanova, Natalia V

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli-Matti

AU - Wu, Anna H

AU - Van Den Berg, David

AU - Lambrechts, Diether

AU - Wildiers, Hans

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Giles, Graham

AU - Milne, Roger L

AU - Haiman, Christopher A

AU - Henderson, Brian E

AU - Dumont, Martine

AU - Teo, Soo-Hwang

AU - Wong, Tien Y

AU - Kristensen, Vessela

AU - Zheng, Wei

AU - Long, Jirong

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Andrulis, Irene L

AU - Knight, Julia A

AU - Devilee, Peter

AU - Seynaeve, Caroline

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Klevebring, Daniel

AU - Czene, Kamila

AU - Hooning, Maartje J

AU - van den Ouweland, Ans M W

AU - Darabi, Hatef

AU - Shu, Xiao-Ou

AU - Gao, Yu-Tang

AU - Cox, Angela

AU - Blot, William

AU - Signorello, Lisa B

AU - Shah, Mitul

AU - Kang, Daehee

AU - Choi, Ji-Yeob

AU - Hartman, Mikael

AU - Miao, Hui

AU - Hamann, Ute

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Sangrajrang, Suleeporn

AU - McKay, James

AU - Toland, Amanda E

AU - Yannoukakos, Drakoulis

AU - Shen, Chen-Yang

AU - Wu, Pei-Ei

AU - Swerdlow, Anthony

AU - Orr, Nick

AU - Simard, Jacques

AU - Pharoah, Paul P D

AU - Dunning, Alison M

AU - Chenevix-Trench, Georgia

AU - Hall, Per

AU - Bandera, Elisa V

AU - Amos, Chris

AU - Ambrosone, Christine B

AU - Easton, Douglas F

AU - Cole, Michael D.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

AB - Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

U2 - 10.1093/hmg/ddw223

DO - 10.1093/hmg/ddw223

M3 - Journal article

C2 - 27402876

SN - 0964-6906

VL - 25

SP - 3863

EP - 3876

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 17

ER -

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

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