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 Schmidt; Rodney 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; German Consortium of Hereditary Breast and Ovarian Cancer

doi:10.1016/j.ajhg.2015.05.002

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, German Consortium of Hereditary Breast and Ovarian Cancer

Institut for Klinisk Medicin

22 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	97
Udgave nummer	1
Sider (fra-til)	22-34
Antal sider	13
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2015.05.002
Status	Udgivet - 1 jul. 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., ... German Consortium of Hereditary Breast and Ovarian Cancer (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

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 & German Consortium of Hereditary Breast and Ovarian Cancer 2015, 'Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression', American Journal of Human Genetics, bind 97, nr. 1, s. 22-34. https://doi.org/10.1016/j.ajhg.2015.05.002

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

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 {German Consortium of Hereditary Breast and Ovarian Cancer}",

year = "2015",

month = jul,

day = "1",

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 = "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 - German Consortium of Hereditary Breast and Ovarian Cancer

PY - 2015/7/1

Y1 - 2015/7/1

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

KW - Body Mass Index

KW - Breast Neoplasms

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 10

KW - DNA-Binding Proteins

KW - Enhancer Elements, Genetic

KW - European Continental Ancestry Group

KW - Female

KW - Gene Expression Regulation

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Luciferases

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Regression Analysis

KW - Trans-Activators

KW - Transcription Factors

U2 - 10.1016/j.ajhg.2015.05.002

DO - 10.1016/j.ajhg.2015.05.002

M3 - Journal 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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