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

Hatef Darabi, Karen McCue, Jonathan Beesley, Kyriaki Michailidou, Silje Nord, Siddhartha Kar, Keith Humphreys, Deborah Thompson, Maya Ghoussaini, Manjeet K. Bolla, Joe Dennis, Qin Wang, Sander Canisius, Christopher G. Scott, Carmel Apicella, John L. Hopper, Melissa C. Southey, Jennifer Stone, Annegien Broeks, Marjanka K. SchmidtRodney J. Scott, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Arif B. Ekici, Peter A. Fasching, Katharina Heusinger, Isabel Dos-Santos-Silva, Julian Peto, Ian Tomlinson, Elinor J. Sawyer, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L. Neuhausen, Volker Arndt, Hermann Brenner, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Norbert Arnold, Hiltrud Brauch, Ute Hamann, Jenny Chang-Claude, Sofia Khan, Heli Nevanlinna, Hidemi Ito, Keitaro Matsuo, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Veli Matti Kosma, Arto Mannermaa, Chiu Chen Tseng, Anna H. Wu, Giuseppe Floris, Diether Lambrechts, Anja Rudolph, Paolo Peterlongo, Paolo Radice, Fergus J Couch, Celine M Vachon, Graham G. Giles, Catriona McLean, Roger L. Milne, Pierre Antoine Dugué, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Brian E. Henderson, Mark S. Goldberg, Jacques Simard, Soo H. Teo, Shivaani Mariapun, Åslaug Helland, Vilde Haakensen, Wei Zheng, Alicia Beeghly-Fadiel, Rulla Tamimi, Arja Jukkola-Vuorinen, Robert Winqvist, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Robert A E M Tollenaar, Jonine Figueroa, Montserrat García-Closas, Kamila Czene, Maartje J. Hooning, Madeleine Tilanus-Linthorst, Jingmei Li, Yu Tang Gao, Xiao Ou Shu, Angela Cox, Simon S. Cross, Robert Luben, Kay Tee Khaw, Ji Yeob Choi, Daehee Kang, Mikael Hartman, Wei Yen Lim, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, James McKay, Suleeporn Sangrajrang, Amanda E. Toland, Drakoulis Yannoukakos, Chen Yang Shen, Jyh Cherng Yu, Argyrios Ziogas, Minouk J. Schoemaker, Anthony Swerdlow, Anne Lise Borresen-Dale, Vessela Kristensen, Juliet D. French, Stacey L. Edwards, Alison M. Dunning, Douglas F. Easton, Per Hall, Georgia Chenevix-Trench

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 languageEnglish (US)
Pages (from-to)22-34
Number of pages13
JournalAmerican Journal of Human Genetics
Volume97
Issue number1
DOIs
StatePublished - 2015

Fingerprint

Single Nucleotide Polymorphism
Breast Neoplasms
Estrogen Receptors
Genome-Wide Association Study
Luciferases
Haplotypes
Transcriptional Activation
Breast
Chromosomes
Epithelial Cells
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Darabi, H., McCue, K., Beesley, J., Michailidou, K., Nord, S., Kar, S., ... Chenevix-Trench, 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

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. / Darabi, Hatef; McCue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Canisius, Sander; Scott, Christopher G.; Apicella, Carmel; Hopper, John L.; Southey, Melissa C.; Stone, Jennifer; Broeks, Annegien; Schmidt, Marjanka K.; Scott, Rodney J.; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W.; Ekici, Arif B.; Fasching, Peter A.; Heusinger, Katharina; Dos-Santos-Silva, Isabel; Peto, Julian; Tomlinson, Ian; Sawyer, Elinor J.; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Arndt, Volker; Brenner, Hermann; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K.; Arnold, Norbert; Brauch, Hiltrud; Hamann, Ute; Chang-Claude, Jenny; Khan, Sofia; Nevanlinna, Heli; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli Matti; Mannermaa, Arto; Tseng, Chiu Chen; Wu, Anna H.; Floris, Giuseppe; Lambrechts, Diether; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Couch, Fergus J; Vachon, Celine M; Giles, Graham G.; McLean, Catriona; Milne, Roger L.; Dugué, Pierre Antoine; Haiman, Christopher A.; Maskarinec, Gertraud; Woolcott, Christy; Henderson, Brian E.; Goldberg, Mark S.; Simard, Jacques; Teo, Soo H.; Mariapun, Shivaani; Helland, Åslaug; Haakensen, Vilde; Zheng, Wei; Beeghly-Fadiel, Alicia; Tamimi, Rulla; Jukkola-Vuorinen, Arja; Winqvist, Robert; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Tollenaar, Robert A E M; Figueroa, Jonine; García-Closas, Montserrat; Czene, Kamila; Hooning, Maartje J.; Tilanus-Linthorst, Madeleine; Li, Jingmei; Gao, Yu Tang; Shu, Xiao Ou; Cox, Angela; Cross, Simon S.; Luben, Robert; Khaw, Kay Tee; Choi, Ji Yeob; Kang, Daehee; Hartman, Mikael; Lim, Wei Yen; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; McKay, James; Sangrajrang, Suleeporn; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen Yang; Yu, Jyh Cherng; Ziogas, Argyrios; Schoemaker, Minouk J.; Swerdlow, Anthony; Borresen-Dale, Anne Lise; Kristensen, Vessela; French, Juliet D.; Edwards, Stacey L.; Dunning, Alison M.; Easton, Douglas F.; Hall, Per; Chenevix-Trench, Georgia.

In: American Journal of Human Genetics, Vol. 97, No. 1, 2015, p. 22-34.

Research output: Contribution to journalArticle

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, CM, Giles, GG, McLean, C, Milne, RL, Dugué, PA, Haiman, CA, Maskarinec, G, Woolcott, C, Henderson, BE, Goldberg, MS, Simard, J, Teo, SH, Mariapun, S, Helland, Å, Haakensen, V, Zheng, W, Beeghly-Fadiel, A, Tamimi, R, Jukkola-Vuorinen, A, Winqvist, R, Andrulis, IL, Knight, JA, Devilee, P, Tollenaar, RAEM, Figueroa, J, García-Closas, M, Czene, K, Hooning, MJ, Tilanus-Linthorst, M, Li, J, Gao, YT, Shu, XO, Cox, A, Cross, SS, Luben, R, Khaw, KT, Choi, JY, Kang, D, Hartman, M, Lim, WY, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, McKay, J, Sangrajrang, S, Toland, AE, Yannoukakos, D, Shen, CY, Yu, JC, Ziogas, A, Schoemaker, MJ, Swerdlow, A, Borresen-Dale, AL, Kristensen, V, French, JD, Edwards, SL, Dunning, AM, Easton, DF, Hall, P & Chenevix-Trench, 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
Darabi, Hatef ; McCue, Karen ; Beesley, Jonathan ; Michailidou, Kyriaki ; Nord, Silje ; Kar, Siddhartha ; Humphreys, Keith ; Thompson, Deborah ; Ghoussaini, Maya ; Bolla, Manjeet K. ; Dennis, Joe ; Wang, Qin ; Canisius, Sander ; Scott, Christopher G. ; Apicella, Carmel ; Hopper, John L. ; Southey, Melissa C. ; Stone, Jennifer ; Broeks, Annegien ; Schmidt, Marjanka K. ; Scott, Rodney J. ; Lophatananon, Artitaya ; Muir, Kenneth ; Beckmann, Matthias W. ; Ekici, Arif B. ; Fasching, Peter A. ; Heusinger, Katharina ; Dos-Santos-Silva, Isabel ; Peto, Julian ; Tomlinson, Ian ; Sawyer, Elinor J. ; Burwinkel, Barbara ; Marme, Frederik ; Guénel, Pascal ; Truong, Thérèse ; Bojesen, Stig E. ; Flyger, Henrik ; Benitez, Javier ; González-Neira, Anna ; Anton-Culver, Hoda ; Neuhausen, Susan L. ; Arndt, Volker ; Brenner, Hermann ; Engel, Christoph ; Meindl, Alfons ; Schmutzler, Rita K. ; Arnold, Norbert ; Brauch, Hiltrud ; Hamann, Ute ; Chang-Claude, Jenny ; Khan, Sofia ; Nevanlinna, Heli ; Ito, Hidemi ; Matsuo, Keitaro ; Bogdanova, Natalia V. ; Dörk, Thilo ; Lindblom, Annika ; Margolin, Sara ; Kosma, Veli Matti ; Mannermaa, Arto ; Tseng, Chiu Chen ; Wu, Anna H. ; Floris, Giuseppe ; Lambrechts, Diether ; Rudolph, Anja ; Peterlongo, Paolo ; Radice, Paolo ; Couch, Fergus J ; Vachon, Celine M ; Giles, Graham G. ; McLean, Catriona ; Milne, Roger L. ; Dugué, Pierre Antoine ; Haiman, Christopher A. ; Maskarinec, Gertraud ; Woolcott, Christy ; Henderson, Brian E. ; Goldberg, Mark S. ; Simard, Jacques ; Teo, Soo H. ; Mariapun, Shivaani ; Helland, Åslaug ; Haakensen, Vilde ; Zheng, Wei ; Beeghly-Fadiel, Alicia ; Tamimi, Rulla ; Jukkola-Vuorinen, Arja ; Winqvist, Robert ; Andrulis, Irene L. ; Knight, Julia A. ; Devilee, Peter ; Tollenaar, Robert A E M ; Figueroa, Jonine ; García-Closas, Montserrat ; Czene, Kamila ; Hooning, Maartje J. ; Tilanus-Linthorst, Madeleine ; Li, Jingmei ; Gao, Yu Tang ; Shu, Xiao Ou ; Cox, Angela ; Cross, Simon S. ; Luben, Robert ; Khaw, Kay Tee ; Choi, Ji Yeob ; Kang, Daehee ; Hartman, Mikael ; Lim, Wei Yen ; Kabisch, Maria ; Torres, Diana ; Jakubowska, Anna ; Lubinski, Jan ; McKay, James ; Sangrajrang, Suleeporn ; Toland, Amanda E. ; Yannoukakos, Drakoulis ; Shen, Chen Yang ; Yu, Jyh Cherng ; Ziogas, Argyrios ; Schoemaker, Minouk J. ; Swerdlow, Anthony ; Borresen-Dale, Anne Lise ; Kristensen, Vessela ; French, Juliet D. ; Edwards, Stacey L. ; Dunning, Alison M. ; Easton, Douglas F. ; Hall, Per ; Chenevix-Trench, Georgia. / Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 1. pp. 22-34.
@article{439f5e12d0394bb488e1d9995057ac06,
title = "Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression",
abstract = "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 = "Hatef Darabi and Karen McCue and Jonathan Beesley and Kyriaki Michailidou and Silje Nord and Siddhartha Kar and Keith Humphreys and Deborah Thompson and Maya Ghoussaini and Bolla, {Manjeet K.} and Joe Dennis and Qin Wang and Sander Canisius and Scott, {Christopher G.} and Carmel Apicella and Hopper, {John L.} and Southey, {Melissa C.} and Jennifer Stone and Annegien Broeks and Schmidt, {Marjanka K.} and Scott, {Rodney J.} and Artitaya Lophatananon and Kenneth Muir and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Fasching, {Peter A.} and Katharina Heusinger and Isabel Dos-Santos-Silva and Julian Peto and Ian Tomlinson and Sawyer, {Elinor J.} and Barbara Burwinkel and Frederik Marme and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E.} and Henrik Flyger and Javier Benitez and Anna Gonz{\'a}lez-Neira and Hoda Anton-Culver and Neuhausen, {Susan L.} and Volker Arndt and Hermann Brenner and Christoph Engel and Alfons Meindl and Schmutzler, {Rita K.} and Norbert Arnold and Hiltrud Brauch and Ute Hamann and Jenny Chang-Claude and Sofia Khan and Heli Nevanlinna and Hidemi Ito and Keitaro Matsuo and Bogdanova, {Natalia V.} and Thilo D{\"o}rk and Annika Lindblom and Sara Margolin and Kosma, {Veli Matti} and Arto Mannermaa and Tseng, {Chiu Chen} and Wu, {Anna H.} and Giuseppe Floris and Diether Lambrechts and Anja Rudolph and Paolo Peterlongo and Paolo Radice and Couch, {Fergus J} and Vachon, {Celine M} and Giles, {Graham G.} and Catriona McLean and Milne, {Roger L.} and Dugu{\'e}, {Pierre Antoine} and Haiman, {Christopher A.} and Gertraud Maskarinec and Christy Woolcott and Henderson, {Brian E.} and Goldberg, {Mark S.} and Jacques Simard and Teo, {Soo H.} and Shivaani Mariapun and {\AA}slaug Helland and Vilde Haakensen and Wei Zheng and Alicia Beeghly-Fadiel and Rulla Tamimi and Arja Jukkola-Vuorinen and Robert Winqvist and Andrulis, {Irene L.} and Knight, {Julia A.} and Peter Devilee and Tollenaar, {Robert A E M} and Jonine Figueroa and Montserrat Garc{\'i}a-Closas and Kamila Czene and Hooning, {Maartje J.} and Madeleine Tilanus-Linthorst and Jingmei Li and Gao, {Yu Tang} and Shu, {Xiao Ou} and Angela Cox and Cross, {Simon S.} and Robert Luben and Khaw, {Kay Tee} and Choi, {Ji Yeob} and Daehee Kang and Mikael Hartman and Lim, {Wei Yen} and Maria Kabisch and Diana Torres and Anna Jakubowska and Jan Lubinski and James McKay and Suleeporn Sangrajrang and Toland, {Amanda E.} and Drakoulis Yannoukakos and Shen, {Chen Yang} and Yu, {Jyh Cherng} and Argyrios Ziogas and Schoemaker, {Minouk J.} and Anthony Swerdlow and Borresen-Dale, {Anne Lise} and Vessela Kristensen and French, {Juliet D.} and Edwards, {Stacey L.} and Dunning, {Alison M.} and Easton, {Douglas F.} and Per Hall and Georgia Chenevix-Trench",
year = "2015",
doi = "10.1016/j.ajhg.2015.05.002",
language = "English (US)",
volume = "97",
pages = "22--34",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

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

AU - Darabi, Hatef

AU - McCue, Karen

AU - Beesley, Jonathan

AU - Michailidou, Kyriaki

AU - Nord, Silje

AU - Kar, Siddhartha

AU - Humphreys, Keith

AU - Thompson, Deborah

AU - Ghoussaini, Maya

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Wang, Qin

AU - Canisius, Sander

AU - Scott, Christopher G.

AU - Apicella, Carmel

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Stone, Jennifer

AU - Broeks, Annegien

AU - Schmidt, Marjanka K.

AU - Scott, Rodney J.

AU - Lophatananon, Artitaya

AU - Muir, Kenneth

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Fasching, Peter A.

AU - Heusinger, Katharina

AU - Dos-Santos-Silva, Isabel

AU - Peto, Julian

AU - Tomlinson, Ian

AU - Sawyer, Elinor J.

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E.

AU - Flyger, Henrik

AU - Benitez, Javier

AU - González-Neira, Anna

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L.

AU - Arndt, Volker

AU - Brenner, Hermann

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Arnold, Norbert

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Chang-Claude, Jenny

AU - Khan, Sofia

AU - Nevanlinna, Heli

AU - Ito, Hidemi

AU - Matsuo, Keitaro

AU - Bogdanova, Natalia V.

AU - Dörk, Thilo

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Kosma, Veli Matti

AU - Mannermaa, Arto

AU - Tseng, Chiu Chen

AU - Wu, Anna H.

AU - Floris, Giuseppe

AU - Lambrechts, Diether

AU - Rudolph, Anja

AU - Peterlongo, Paolo

AU - Radice, Paolo

AU - Couch, Fergus J

AU - Vachon, Celine M

AU - Giles, Graham G.

AU - McLean, Catriona

AU - Milne, Roger L.

AU - Dugué, Pierre Antoine

AU - Haiman, Christopher A.

AU - Maskarinec, Gertraud

AU - Woolcott, Christy

AU - Henderson, Brian E.

AU - Goldberg, Mark S.

AU - Simard, Jacques

AU - Teo, Soo H.

AU - Mariapun, Shivaani

AU - Helland, Åslaug

AU - Haakensen, Vilde

AU - Zheng, Wei

AU - Beeghly-Fadiel, Alicia

AU - Tamimi, Rulla

AU - Jukkola-Vuorinen, Arja

AU - Winqvist, Robert

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Devilee, Peter

AU - Tollenaar, Robert A E M

AU - Figueroa, Jonine

AU - García-Closas, Montserrat

AU - Czene, Kamila

AU - Hooning, Maartje J.

AU - Tilanus-Linthorst, Madeleine

AU - Li, Jingmei

AU - Gao, Yu Tang

AU - Shu, Xiao Ou

AU - Cox, Angela

AU - Cross, Simon S.

AU - Luben, Robert

AU - Khaw, Kay Tee

AU - Choi, Ji Yeob

AU - Kang, Daehee

AU - Hartman, Mikael

AU - Lim, Wei Yen

AU - Kabisch, Maria

AU - Torres, Diana

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - McKay, James

AU - Sangrajrang, Suleeporn

AU - Toland, Amanda E.

AU - Yannoukakos, Drakoulis

AU - Shen, Chen Yang

AU - Yu, Jyh Cherng

AU - Ziogas, Argyrios

AU - Schoemaker, Minouk J.

AU - Swerdlow, Anthony

AU - Borresen-Dale, Anne Lise

AU - Kristensen, Vessela

AU - French, Juliet D.

AU - Edwards, Stacey L.

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Hall, Per

AU - Chenevix-Trench, Georgia

PY - 2015

Y1 - 2015

N2 - 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 - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937521559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937521559&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.05.002

DO - 10.1016/j.ajhg.2015.05.002

M3 - Article

C2 - 26073781

AN - SCOPUS:84937521559

VL - 97

SP - 22

EP - 34

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -