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; J 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 Guenel; T Truong; S E Bojesen; H Flyger; J Benitez; A Gonzalez-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 Dork; 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 Dugue; C A Haiman; G Maskarinec; C Woolcott; B E Henderson; M S Goldberg; J Simard; S H Teo; S Mariapun; A Helland; V Haakensen; W Zheng; A Beeghly-Fadiel; R Tamimi; A Jukkola-Vuorinen; R Winqvist; I L Andrulis; J A Knight; P Devilee; R A Tollenaar; J Figueroa; M Garcia-Closas; K Czene; M J Hooning; M Tilanus-Linthorst; J Li; Y T Gao; X O Shu; A Cox; S S Cross; R Luben; K T Khaw; J Y Choi; D Kang; M Hartman; W Y Lim; M Kabisch; D Torres; A Jakubowska; J Lubinski; J McKay; S Sangrajrang; A E Toland; D Yannoukakos; C Y Shen; J C Yu; A Ziogas; M J Schoemaker; A Swerdlow; A L Borresen-Dale; V Kristensen; J D French; S L Edwards; A M Dunning; D F Easton; P Hall; G Chenevix-Trench

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, J 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 Guenel, T Truong, S E Bojesen, H Flyger, J Benitez, A Gonzalez-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 Dork, 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 Dugue, C A Haiman, G Maskarinec, C Woolcott, B E Henderson, M S Goldberg, J Simard, S H Teo, S Mariapun, A Helland, V Haakensen, W Zheng, A Beeghly-Fadiel, R Tamimi, A Jukkola-Vuorinen, R Winqvist, I L Andrulis, J A Knight, P Devilee, R A Tollenaar, J Figueroa, M Garcia-Closas, K Czene, M J Hooning, M Tilanus-Linthorst, J Li, Y T Gao, X O Shu, A Cox, S S Cross, R Luben, K T Khaw, J Y Choi, D Kang, M Hartman, W Y Lim, M Kabisch, D Torres, A Jakubowska, J Lubinski, J McKay, S Sangrajrang, A E Toland, D Yannoukakos, C Y Shen, J C Yu, A Ziogas, M J Schoemaker, A Swerdlow, A L Borresen-Dale, V Kristensen, J D French, S L Edwards, A M Dunning, D F Easton, P Hall, G Chenevix-Trench

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

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 language	English
Pages (from-to)	22-34
Number of pages	13
Journal	Am J Hum Genet
Volume	97
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2015.05.002
Publication status	Published - 2015

Keywords

Age Factors
Asian Continental Ancestry Group/genetics
Body Mass Index
Breast Neoplasms/ genetics
Chromosome Mapping
Chromosomes, Human, Pair 10/ genetics
DNA-Binding Proteins/ genetics
Enhancer Elements, Genetic/ genetics
European Continental Ancestry Group/genetics
Female
Gene Expression Regulation/ genetics
Genome-Wide Association Study
Genotype
Humans
Luciferases
Odds Ratio
Polymorphism, Single Nucleotide/genetics
Quantitative Trait Loci/genetics
Regression Analysis
Trans-Activators/ genetics/metabolism
Transcription Factors/ genetics

UN SDGs

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

Access to Document

10.1016/j.ajhg.2015.05.002

Cite this

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., ... Chenevix-Trench, G. (2015). Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. Am J Hum Genet, 97(1), 22-34. https://doi.org/10.1016/j.ajhg.2015.05.002

@article{d99820eb5be8431083e731858c375c45,

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.",

keywords = "Age Factors, Asian Continental Ancestry Group/genetics, Body Mass Index, Breast Neoplasms/ genetics, Chromosome Mapping, Chromosomes, Human, Pair 10/ genetics, DNA-Binding Proteins/ genetics, Enhancer Elements, Genetic/ genetics, European Continental Ancestry Group/genetics, Female, Gene Expression Regulation/ genetics, Genome-Wide Association Study, Genotype, Humans, Luciferases, Odds Ratio, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Regression Analysis, Trans-Activators/ genetics/metabolism, Transcription Factors/ genetics",

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 Bolla, {M K} and J Dennis and Q Wang and S Canisius and Scott, {C G} and C Apicella and Hopper, {J L} and Southey, {M C} and J Stone and A Broeks and Schmidt, {M K} and Scott, {R J} and A Lophatananon and K Muir and Beckmann, {M W} and Ekici, {A B} and Fasching, {P A} and K Heusinger and I Dos-Santos-Silva and J Peto and I Tomlinson and Sawyer, {E J} and B Burwinkel and F Marme and P Guenel and T Truong and Bojesen, {S E} and H Flyger and J Benitez and A Gonzalez-Neira and H Anton-Culver and Neuhausen, {S L} and V Arndt and H Brenner and C Engel and A Meindl and Schmutzler, {R K} 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 Bogdanova, {N V} and T Dork and A Lindblom and S Margolin and Kosma, {V M} and A Mannermaa and Tseng, {C C} and Wu, {A H} and G Floris and D Lambrechts and A Rudolph and P Peterlongo and P Radice and Couch, {F J} and C Vachon and Giles, {G G} and C McLean and Milne, {R L} and Dugue, {P A} and Haiman, {C A} and G Maskarinec and C Woolcott and Henderson, {B E} and Goldberg, {M S} and J Simard and Teo, {S H} and S Mariapun and A Helland and V Haakensen and W Zheng and A Beeghly-Fadiel and R Tamimi and A Jukkola-Vuorinen and R Winqvist and Andrulis, {I L} and Knight, {J A} and P Devilee and Tollenaar, {R A} and J Figueroa and M Garcia-Closas and K Czene and Hooning, {M J} and M Tilanus-Linthorst and J Li and Gao, {Y T} and Shu, {X O} and A Cox and Cross, {S S} and R Luben and Khaw, {K T} and Choi, {J Y} and D Kang and M Hartman and Lim, {W Y} and M Kabisch and D Torres and A Jakubowska and J Lubinski and J McKay and S Sangrajrang and Toland, {A E} and D Yannoukakos and Shen, {C Y} and Yu, {J C} and A Ziogas and Schoemaker, {M J} and A Swerdlow and Borresen-Dale, {A L} and V Kristensen and French, {J D} and Edwards, {S L} and Dunning, {A M} and Easton, {D F} and P Hall and G Chenevix-Trench",

note = "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 Guenel, Pascal Truong, Therese Bojesen, Stig E Flyger, Henrik Benitez, Javier Gonzalez-Neira, Anna Anton-Culver, Hoda Neuhausen, Susan L Arndt, Volker Brenner, Hermann Engel, Christoph Meindl, Alfons Schmutzler, Rita K German Consortium of Hereditary Breast and Ovarian Cancer Arnold, Norbert Brauch, Hiltrud Hamann, Ute Chang-Claude, Jenny Khan, Sofia Nevanlinna, Heli Ito, Hidemi Matsuo, Keitaro Bogdanova, Natalia V Dork, Thilo Lindblom, Annika Margolin, Sara kConFab/AOCS Investigators 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 Giles, Graham G McLean, Catriona Milne, Roger L Dugue, Pierre-Antoine Haiman, Christopher A Maskarinec, Gertraud Woolcott, Christy Henderson, Brian E Goldberg, Mark S Simard, Jacques Teo, Soo H Mariapun, Shivaani Helland, Aslaug 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 Garcia-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 14136/Cancer Research UK/United Kingdom United States American journal of human genetics Am J Hum Genet. 2015 Jul 2;97(1):22-34. doi: 10.1016/j.ajhg.2015.05.002. Epub 2015 Jun 11.",

year = "2015",

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

language = "English",

volume = "97",

pages = "22--34",

journal = "Am J Hum Genet",

issn = "0002-9297",

publisher = "Cell 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, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, Gonzalez-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, Dork, 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, Dugue, PA, Haiman, CA, Maskarinec, G, Woolcott, C, Henderson, BE, Goldberg, MS, Simard, J, Teo, SH, Mariapun, S, Helland, A, Haakensen, V, Zheng, W, Beeghly-Fadiel, A, Tamimi, R, Jukkola-Vuorinen, A, Winqvist, R, Andrulis, IL, Knight, JA, Devilee, P, Tollenaar, RA, Figueroa, J, Garcia-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', Am J Hum Genet, 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, J

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 - Guenel, P

AU - Truong, T

AU - Bojesen, S E

AU - Flyger, H

AU - Benitez, J

AU - Gonzalez-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 - Dork, 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 - Dugue, P A

AU - Haiman, C A

AU - Maskarinec, G

AU - Woolcott, C

AU - Henderson, B E

AU - Goldberg, M S

AU - Simard, J

AU - Teo, S H

AU - Mariapun, S

AU - Helland, A

AU - Haakensen, V

AU - Zheng, W

AU - Beeghly-Fadiel, A

AU - Tamimi, R

AU - Jukkola-Vuorinen, A

AU - Winqvist, R

AU - Andrulis, I L

AU - Knight, J A

AU - Devilee, P

AU - Tollenaar, R A

AU - Figueroa, J

AU - Garcia-Closas, M

AU - Czene, K

AU - Hooning, M J

AU - Tilanus-Linthorst, M

AU - Li, J

AU - Gao, Y T

AU - Shu, X O

AU - Cox, A

AU - Cross, S S

AU - Luben, R

AU - Khaw, K T

AU - Choi, J Y

AU - Kang, D

AU - Hartman, M

AU - Lim, W Y

AU - Kabisch, M

AU - Torres, D

AU - Jakubowska, A

AU - Lubinski, J

AU - McKay, J

AU - Sangrajrang, S

AU - Toland, A E

AU - Yannoukakos, D

AU - Shen, C Y

AU - Yu, J C

AU - Ziogas, A

AU - Schoemaker, M J

AU - Swerdlow, A

AU - Borresen-Dale, A L

AU - Kristensen, V

AU - French, J D

AU - Edwards, S L

AU - Dunning, A M

AU - Easton, D F

AU - Hall, P

AU - Chenevix-Trench, G

N1 - 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 Guenel, Pascal Truong, Therese Bojesen, Stig E Flyger, Henrik Benitez, Javier Gonzalez-Neira, Anna Anton-Culver, Hoda Neuhausen, Susan L Arndt, Volker Brenner, Hermann Engel, Christoph Meindl, Alfons Schmutzler, Rita K German Consortium of Hereditary Breast and Ovarian Cancer Arnold, Norbert Brauch, Hiltrud Hamann, Ute Chang-Claude, Jenny Khan, Sofia Nevanlinna, Heli Ito, Hidemi Matsuo, Keitaro Bogdanova, Natalia V Dork, Thilo Lindblom, Annika Margolin, Sara kConFab/AOCS Investigators 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 Giles, Graham G McLean, Catriona Milne, Roger L Dugue, Pierre-Antoine Haiman, Christopher A Maskarinec, Gertraud Woolcott, Christy Henderson, Brian E Goldberg, Mark S Simard, Jacques Teo, Soo H Mariapun, Shivaani Helland, Aslaug 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 Garcia-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 14136/Cancer Research UK/United Kingdom United States American journal of human genetics Am J Hum Genet. 2015 Jul 2;97(1):22-34. doi: 10.1016/j.ajhg.2015.05.002. Epub 2015 Jun 11.

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.

KW - Age Factors

KW - Asian Continental Ancestry Group/genetics

KW - Body Mass Index

KW - Breast Neoplasms/ genetics

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 10/ genetics

KW - DNA-Binding Proteins/ genetics

KW - Enhancer Elements, Genetic/ genetics

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Gene Expression Regulation/ genetics

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Luciferases

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait Loci/genetics

KW - Regression Analysis

KW - Trans-Activators/ genetics/metabolism

KW - Transcription Factors/ genetics

U2 - 10.1016/j.ajhg.2015.05.002

DO - 10.1016/j.ajhg.2015.05.002

M3 - Article

SN - 0002-9297

VL - 97

SP - 22

EP - 34

JO - Am J Hum Genet

JF - Am J Hum Genet

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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