Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

Xingyi Guo; Jirong Long; Chenjie Zeng; Kyriaki Michailidou; Maya Ghoussaini; Manjeet K Bolla; Qin Wang; Roger L Milne; Xiao-Ou Shu; Qiuyin Cai; Jonathan Beesley; Siddhartha P Kar; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Matthias W Beckmann; Alicia Beeghly-Fadiel; Javier Benitez; William Blot; Natalia Bogdanova; Stig E Bojesen; Hiltrud Brauch; Hermann Brenner; Louise Brinton; Annegien Broeks; Thomas Brüning; Barbara Burwinkel; Hui Cai; Sander Canisius; Jenny Chang-Claude; Ji-Yeob Choi; Fergus J Couch; Angela Cox; Simon S Cross; Kamila Czene; Hatef Darabi; Peter Devilee; Arnaud Droit; Thilo Dörk; Peter A Fasching; Olivia Fletcher; Henrik Flyger; Florentia Fostira; Valerie Gaborieau; Montserrat García-Closas; Graham G Giles; Mervi Grip; Pascal Guénel; Christopher A Haiman; Ute Hamann; kConFab Investigators

doi:10.1158/1055-9965.epi-15-0363

Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

Xingyi Guo, Jirong Long, Chenjie Zeng, Kyriaki Michailidou, Maya Ghoussaini, Manjeet K Bolla, Qin Wang, Roger L Milne, Xiao-Ou Shu, Qiuyin Cai, Jonathan Beesley, Siddhartha P Kar, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, William Blot, Natalia BogdanovaStig E Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Hui Cai, Sander Canisius, Jenny Chang-Claude, Ji-Yeob Choi, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Arnaud Droit, Thilo Dörk, Peter A Fasching, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Valerie Gaborieau, Montserrat García-Closas, Graham G Giles, Mervi Grip, Pascal Guénel, Christopher A Haiman, Ute Hamann, kConFab Investigators

Department of Clinical Medicine

15 Citations (Scopus)

Abstract

BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.

METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.

RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.

CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.

IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

Original language	English
Journal	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume	24
Issue number	11
Pages (from-to)	1680-91
Number of pages	12
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.epi-15-0363
Publication status	Published - 1 Nov 2015

UN SDGs

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

Access to Document

10.1158/1055-9965.epi-15-0363

1680.full.pdfFinal published version, 1.37 MB

Cite this

Guo, X., Long, J., Zeng, C., Michailidou, K., Ghoussaini, M., Bolla, M. K., Wang, Q., Milne, R. L., Shu, X.-O., Cai, Q., Beesley, J., Kar, S. P., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Blot, W., ... kConFab Investigators (2015). Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 24(11), 1680-91. https://doi.org/10.1158/1055-9965.epi-15-0363

Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk. / Guo, Xingyi; Long, Jirong; Zeng, Chenjie et al.
In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 24, No. 11, 01.11.2015, p. 1680-91.

Research output: Contribution to journal › Journal article › Research › peer-review

Guo, X, Long, J, Zeng, C, Michailidou, K, Ghoussaini, M, Bolla, MK, Wang, Q, Milne, RL, Shu, X-O, Cai, Q, Beesley, J, Kar, SP, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Blot, W, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Brinton, L, Broeks, A, Brüning, T, Burwinkel, B, Cai, H, Canisius, S, Chang-Claude, J, Choi, J-Y, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Droit, A, Dörk, T, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Gaborieau, V, García-Closas, M, Giles, GG, Grip, M, Guénel, P, Haiman, CA, Hamann, U & kConFab Investigators 2015, 'Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 24, no. 11, pp. 1680-91. https://doi.org/10.1158/1055-9965.epi-15-0363

Guo X, Long J, Zeng C, Michailidou K, Ghoussaini M, Bolla MK et al. Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 Nov 1;24(11):1680-91. doi: 10.1158/1055-9965.epi-15-0363

@article{ad6e102537f54b84829db3da9ea26d07,

title = "Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk",

abstract = "BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.",

author = "Xingyi Guo and Jirong Long and Chenjie Zeng and Kyriaki Michailidou and Maya Ghoussaini and Bolla, {Manjeet K} and Qin Wang and Milne, {Roger L} and Xiao-Ou Shu and Qiuyin Cai and Jonathan Beesley and Kar, {Siddhartha P} and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Beckmann, {Matthias W} and Alicia Beeghly-Fadiel and Javier Benitez and William Blot and Natalia Bogdanova and Bojesen, {Stig E} and Hiltrud Brauch and Hermann Brenner and Louise Brinton and Annegien Broeks and Thomas Br{\"u}ning and Barbara Burwinkel and Hui Cai and Sander Canisius and Jenny Chang-Claude and Ji-Yeob Choi and Couch, {Fergus J} and Angela Cox and Cross, {Simon S} and Kamila Czene and Hatef Darabi and Peter Devilee and Arnaud Droit and Thilo D{\"o}rk and Fasching, {Peter A} and Olivia Fletcher and Henrik Flyger and Florentia Fostira and Valerie Gaborieau and Montserrat Garc{\'i}a-Closas and Giles, {Graham G} and Mervi Grip and Pascal Gu{\'e}nel and Haiman, {Christopher A} and Ute Hamann and {kConFab Investigators}",

note = "{\textcopyright}2015 American Association for Cancer Research.",

year = "2015",

month = nov,

day = "1",

doi = "10.1158/1055-9965.epi-15-0363",

language = "English",

volume = "24",

pages = "1680--91",

journal = "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "11",

}

TY - JOUR

T1 - Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

AU - Guo, Xingyi

AU - Long, Jirong

AU - Zeng, Chenjie

AU - Michailidou, Kyriaki

AU - Ghoussaini, Maya

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Milne, Roger L

AU - Shu, Xiao-Ou

AU - Cai, Qiuyin

AU - Beesley, Jonathan

AU - Kar, Siddhartha P

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Beckmann, Matthias W

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Blot, William

AU - Bogdanova, Natalia

AU - Bojesen, Stig E

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brinton, Louise

AU - Broeks, Annegien

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Cai, Hui

AU - Canisius, Sander

AU - Chang-Claude, Jenny

AU - Choi, Ji-Yeob

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Devilee, Peter

AU - Droit, Arnaud

AU - Dörk, Thilo

AU - Fasching, Peter A

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Fostira, Florentia

AU - Gaborieau, Valerie

AU - García-Closas, Montserrat

AU - Giles, Graham G

AU - Grip, Mervi

AU - Guénel, Pascal

AU - Haiman, Christopher A

AU - Hamann, Ute

AU - kConFab Investigators

PY - 2015/11/1

Y1 - 2015/11/1

N2 - BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

AB - BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

U2 - 10.1158/1055-9965.epi-15-0363

DO - 10.1158/1055-9965.epi-15-0363

M3 - Journal article

C2 - 26354892

SN - 1055-9965

VL - 24

SP - 1680

EP - 1691

JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

IS - 11

ER -

Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this