Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

H. Darabi; K. Mccue; J. Beesley; K. Michailidou; S. Nord; S. Kar; K. Humphreys; D. Thompson; M. Ghoussaini; M.K. Bolla; J. Dennis; Q. Wang; S. Canisius; C.G. Scott; C. Apicella; J.L. Hopper; M.C. Southey; Jennifer Stone; A. Broeks; M.K. Schmidt; R.J. Scott; A. Lophatananon; K. Muir; M.W. Beckmann; A.B. Ekici; P.A. Fasching; K. Heusinger; I. Dos-Santos-Silva; J. Peto; I. Tomlinson; E.J. Sawyer; B. Burwinkel; F. Marme; P. Guénel; T. Truong; S.E. Bojesen; H. Flyger; J. Benitez; A. González-Neira; H. Anton-Culver; S.L. Neuhausen; V. Arndt; H. Brenner; C. Engel; A. Meindl; R.K. Schmutzler; N. Arnold; H. Brauch; U. Hamann; J. Chang-Claude; S. Khan; H. Nevanlinna; H. Ito; K. Matsuo; N.V. Bogdanova; T. Dörk; A. Lindblom; S. Margolin; V.M. Kosma; A. Mannermaa; C.C. Tseng; A.H. Wu; G. Floris; D. Lambrechts; A. Rudolph; P. Peterlongo; P. Radice; F.J. Couch; C. Vachon; G.G. Giles; C. Mclean; R.L. Milne; P.A. Dugué; C.A. Haiman; G. Maskarinec

doi:10.1016/j.ajhg.2015.05.002

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

H. Darabi, K. Mccue, J. Beesley, K. Michailidou, S. Nord, S. Kar, K. Humphreys, D. Thompson, M. Ghoussaini, M.K. Bolla, J. Dennis, Q. Wang, S. Canisius, C.G. Scott, C. Apicella, J.L. Hopper, M.C. Southey, Jennifer Stone, A. Broeks, M.K. SchmidtR.J. Scott, A. Lophatananon, K. Muir, M.W. Beckmann, A.B. Ekici, P.A. Fasching, K. Heusinger, I. Dos-Santos-Silva, J. Peto, I. Tomlinson, E.J. Sawyer, B. Burwinkel, F. Marme, P. Guénel, T. Truong, S.E. Bojesen, H. Flyger, J. Benitez, A. González-Neira, H. Anton-Culver, S.L. Neuhausen, V. Arndt, H. Brenner, C. Engel, A. Meindl, R.K. Schmutzler, N. Arnold, H. Brauch, U. Hamann, J. Chang-Claude, S. Khan, H. Nevanlinna, H. Ito, K. Matsuo, N.V. Bogdanova, T. Dörk, A. Lindblom, S. Margolin, V.M. Kosma, A. Mannermaa, C.C. Tseng, A.H. Wu, G. Floris, D. Lambrechts, A. Rudolph, P. Peterlongo, P. Radice, F.J. Couch, C. Vachon, G.G. Giles, C. Mclean, R.L. Milne, P.A. Dugué, C.A. Haiman, G. Maskarinec

Centre for Genetic Origins of Health and Diseases

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32 Citations (Scopus)

Abstract

© 2015 The American Society of Human Genetics. Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Original language	English
Pages (from-to)	22-34
Journal	American Journal of Human Genetics
Volume	97
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2015.05.002
Publication status	Published - 2015

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10.1016/j.ajhg.2015.05.002

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Darabi, H., Mccue, K., Beesley, J., Michailidou, K., Nord, S., Kar, S., Humphreys, K., Thompson, D., Ghoussaini, M., Bolla, M. K., Dennis, J., Wang, Q., Canisius, S., Scott, C. G., Apicella, C., Hopper, J. L., Southey, M. C., Stone, J., Broeks, A., ... Maskarinec, G. (2015). Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. American Journal of Human Genetics, 97(1), 22-34. https://doi.org/10.1016/j.ajhg.2015.05.002

@article{85307928059e4c08a394ef2b4688847a,

title = "Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression",

abstract = "{\textcopyright} 2015 The American Society of Human Genetics. Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.",

author = "H. Darabi and K. Mccue and J. Beesley and K. Michailidou and S. Nord and S. Kar and K. Humphreys and D. Thompson and M. Ghoussaini and M.K. Bolla and J. Dennis and Q. Wang and S. Canisius and C.G. Scott and C. Apicella and J.L. Hopper and M.C. Southey and Jennifer Stone and A. Broeks and M.K. Schmidt and R.J. Scott and A. Lophatananon and K. Muir and M.W. Beckmann and A.B. Ekici and P.A. Fasching and K. Heusinger and I. Dos-Santos-Silva and J. Peto and I. Tomlinson and E.J. Sawyer and B. Burwinkel and F. Marme and P. Gu{\'e}nel and T. Truong and S.E. Bojesen and H. Flyger and J. Benitez and A. Gonz{\'a}lez-Neira and H. Anton-Culver and S.L. Neuhausen and V. Arndt and H. Brenner and C. Engel and A. Meindl and R.K. Schmutzler and N. Arnold and H. Brauch and U. Hamann and J. Chang-Claude and S. Khan and H. Nevanlinna and H. Ito and K. Matsuo and N.V. Bogdanova and T. D{\"o}rk and A. Lindblom and S. Margolin and V.M. Kosma and A. Mannermaa and C.C. Tseng and A.H. Wu and G. Floris and D. Lambrechts and A. Rudolph and P. Peterlongo and P. Radice and F.J. Couch and C. Vachon and G.G. Giles and C. Mclean and R.L. Milne and P.A. Dugu{\'e} and C.A. Haiman and G. Maskarinec",

year = "2015",

doi = "10.1016/j.ajhg.2015.05.002",

language = "English",

volume = "97",

pages = "22--34",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "UNIV CHICAGO PRESS",

number = "1",

}

Darabi, H, Mccue, K, Beesley, J, Michailidou, K, Nord, S, Kar, S, Humphreys, K, Thompson, D, Ghoussaini, M, Bolla, MK, Dennis, J, Wang, Q, Canisius, S, Scott, CG, Apicella, C, Hopper, JL, Southey, MC, Stone, J, Broeks, A, Schmidt, MK, Scott, RJ, Lophatananon, A, Muir, K, Beckmann, MW, Ekici, AB, Fasching, PA, Heusinger, K, Dos-Santos-Silva, I, Peto, J, Tomlinson, I, Sawyer, EJ, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, González-Neira, A, Anton-Culver, H, Neuhausen, SL, Arndt, V, Brenner, H, Engel, C, Meindl, A, Schmutzler, RK, Arnold, N, Brauch, H, Hamann, U, Chang-Claude, J, Khan, S, Nevanlinna, H, Ito, H, Matsuo, K, Bogdanova, NV, Dörk, T, Lindblom, A, Margolin, S, Kosma, VM, Mannermaa, A, Tseng, CC, Wu, AH, Floris, G, Lambrechts, D, Rudolph, A, Peterlongo, P, Radice, P, Couch, FJ, Vachon, C, Giles, GG, Mclean, C, Milne, RL, Dugué, PA, Haiman, CA & Maskarinec, G 2015, 'Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression', American Journal of Human Genetics, vol. 97, no. 1, pp. 22-34. https://doi.org/10.1016/j.ajhg.2015.05.002

TY - JOUR

T1 - Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

AU - Darabi, H.

AU - Mccue, K.

AU - Beesley, J.

AU - Michailidou, K.

AU - Nord, S.

AU - Kar, S.

AU - Humphreys, K.

AU - Thompson, D.

AU - Ghoussaini, M.

AU - Bolla, M.K.

AU - Dennis, J.

AU - Wang, Q.

AU - Canisius, S.

AU - Scott, C.G.

AU - Apicella, C.

AU - Hopper, J.L.

AU - Southey, M.C.

AU - Stone, Jennifer

AU - Broeks, A.

AU - Schmidt, M.K.

AU - Scott, R.J.

AU - Lophatananon, A.

AU - Muir, K.

AU - Beckmann, M.W.

AU - Ekici, A.B.

AU - Fasching, P.A.

AU - Heusinger, K.

AU - Dos-Santos-Silva, I.

AU - Peto, J.

AU - Tomlinson, I.

AU - Sawyer, E.J.

AU - Burwinkel, B.

AU - Marme, F.

AU - Guénel, P.

AU - Truong, T.

AU - Bojesen, S.E.

AU - Flyger, H.

AU - Benitez, J.

AU - González-Neira, A.

AU - Anton-Culver, H.

AU - Neuhausen, S.L.

AU - Arndt, V.

AU - Brenner, H.

AU - Engel, C.

AU - Meindl, A.

AU - Schmutzler, R.K.

AU - Arnold, N.

AU - Brauch, H.

AU - Hamann, U.

AU - Chang-Claude, J.

AU - Khan, S.

AU - Nevanlinna, H.

AU - Ito, H.

AU - Matsuo, K.

AU - Bogdanova, N.V.

AU - Dörk, T.

AU - Lindblom, A.

AU - Margolin, S.

AU - Kosma, V.M.

AU - Mannermaa, A.

AU - Tseng, C.C.

AU - Wu, A.H.

AU - Floris, G.

AU - Lambrechts, D.

AU - Rudolph, A.

AU - Peterlongo, P.

AU - Radice, P.

AU - Couch, F.J.

AU - Vachon, C.

AU - Giles, G.G.

AU - Mclean, C.

AU - Milne, R.L.

AU - Dugué, P.A.

AU - Haiman, C.A.

AU - Maskarinec, G.

PY - 2015

Y1 - 2015

N2 - © 2015 The American Society of Human Genetics. Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

AB - © 2015 The American Society of Human Genetics. Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

U2 - 10.1016/j.ajhg.2015.05.002

DO - 10.1016/j.ajhg.2015.05.002

M3 - Article

C2 - 26073781

SN - 0002-9297

VL - 97

SP - 22

EP - 34

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

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