Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

XY Guo; JR Long; CJ Zeng; K Michailidou; M Ghoussaini; MK Bolla; Q (Qing) Wang; RL Milne; XO Shu; QY Cai; J Beesley; SP Kar; IL Andrulis; H Anton-Culver; V Arndt; MW Beckmann; A Beeghly-Fadiel; J Benitez; W Blot; N Bogdanova; SE Bojesen; H Brauch; H Brenner; L Brinton; A Broeks; T Bruning; B Burwinkel; H Cai; S Canisius; J Chang-Claude; JY Choi; FJ Couch; A Cox; SS Cross; K Czene; H Darabi; P Devilee; A Droit; T Dork; PA Fasching; O Fletcher; H Flyger; F Fostira; V Gaborieau; M Garcia-Closas; GG Giles; M Grip; P Guenel; CA Haiman; U Hamann; M Hartman; Antoinette Hollestelle; JL Hopper; CN Hsiung; H Ito; A Jakubowska; N Johnson; M Kabisch; D Kang; Salima Khan; JA Knight; VM Kosma; D Lambrechts; L Le Marchand; JM Li; A Lindblom; A Lophatananon; J Lubinski; A Mannermaa; S Manoukian; S Margolin; F Marme; K Matsuo; CA McLean; A Meindl; K Muir; SL Neuhausen; H Nevanlinna; S Nord; JE Olson; N Orr; P Peterlongo; TC Putti; A Rudolph; S Sangrajrang; EJ Sawyer; MK (Marjanka) Schmidt; RK Schmutzler; CY Shen; JJ Shi; MJ Shrubsole; MC Southey; A Swerdlow; SH Teo; B Thienpont; AE Toland; RAEM Tollenaar; IPM Tomlinson; T Truong; CC Tseng; Ans van den Ouweland; WQ Wen; R Winqvist; A Wu; CH Yip; MP Zamora; Y Zheng; P Hall; PDP Pharoah; J Simard; G Chenevix-Trench; AM Dunning; DF Easton; W Zheng

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

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

XY Guo, JR Long, CJ Zeng, K Michailidou, M Ghoussaini, MK Bolla, Q (Qing) Wang, RL Milne, XO Shu, QY Cai, J Beesley, SP Kar, IL Andrulis, H Anton-Culver, V Arndt, MW Beckmann, A Beeghly-Fadiel, J Benitez, W Blot, N BogdanovaSE Bojesen, H Brauch, H Brenner, L Brinton, A Broeks, T Bruning, B Burwinkel, H Cai, S Canisius, J Chang-Claude, JY Choi, FJ Couch, A Cox, SS Cross, K Czene, H Darabi, P Devilee, A Droit, T Dork, PA Fasching, O Fletcher, H Flyger, F Fostira, V Gaborieau, M Garcia-Closas, GG Giles, M Grip, P Guenel, CA Haiman, U Hamann, M Hartman, Antoinette Hollestelle, JL Hopper, CN Hsiung, H Ito, A Jakubowska, N Johnson, M Kabisch, D Kang, Salima Khan, JA Knight, VM Kosma, D Lambrechts, L Le Marchand, JM Li, A Lindblom, A Lophatananon, J Lubinski, A Mannermaa, S Manoukian, S Margolin, F Marme, K Matsuo, CA McLean, A Meindl, K Muir, SL Neuhausen, H Nevanlinna, S Nord, JE Olson, N Orr, P Peterlongo, TC Putti, A Rudolph, S Sangrajrang, EJ Sawyer, MK (Marjanka) Schmidt, RK Schmutzler, CY Shen, JJ Shi, MJ Shrubsole, MC Southey, A Swerdlow, SH Teo, B Thienpont, AE Toland, RAEM Tollenaar, IPM Tomlinson, T Truong, CC Tseng, Ans van den Ouweland, WQ Wen, R Winqvist, A Wu, CH Yip, MP Zamora, Y Zheng, P Hall, PDP Pharoah, J Simard, G Chenevix-Trench, AM Dunning, DF Easton, W Zheng

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

23 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 x 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 x 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. (C) 2015 AACR.

Original language	Undefined/Unknown
Pages (from-to)	1680-1691
Number of pages	12
Journal	Cancer Epidemiology Biomarkers & Prevention
Volume	24
Issue number	11
DOIs	https://doi.org/10.1158/1055-9965.EPI-15-0363
Publication status	Published - 2015

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10.1158/1055-9965.EPI-15-0363

Cite this

Guo, XY., Long, JR., Zeng, CJ., Michailidou, K., Ghoussaini, M., Bolla, MK., Wang, Q., Milne, RL., Shu, XO., Cai, QY., Beesley, J., Kar, SP., Andrulis, IL., Anton-Culver, H., Arndt, V., Beckmann, MW., Beeghly-Fadiel, A., Benitez, J., Blot, W., ... Zheng, W. (2015). Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk. Cancer Epidemiology Biomarkers & Prevention, 24(11), 1680-1691. https://doi.org/10.1158/1055-9965.EPI-15-0363

@article{549f2e3e357e4758a7196f387356de17,

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 x 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 x 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. (C) 2015 AACR.",

author = "XY Guo and JR Long and CJ Zeng and K Michailidou and M Ghoussaini and MK Bolla and Wang, {Q (Qing)} and RL Milne and XO Shu and QY Cai and J Beesley and SP Kar and IL Andrulis and H Anton-Culver and V Arndt and MW Beckmann and A Beeghly-Fadiel and J Benitez and W Blot and N Bogdanova and SE Bojesen and H Brauch and H Brenner and L Brinton and A Broeks and T Bruning and B Burwinkel and H Cai and S Canisius and J Chang-Claude and JY Choi and FJ Couch and A Cox and SS Cross and K Czene and H Darabi and P Devilee and A Droit and T Dork and PA Fasching and O Fletcher and H Flyger and F Fostira and V Gaborieau and M Garcia-Closas and GG Giles and M Grip and P Guenel and CA Haiman and U Hamann and M Hartman and Antoinette Hollestelle and JL Hopper and CN Hsiung and H Ito and A Jakubowska and N Johnson and M Kabisch and D Kang and Salima Khan and JA Knight and VM Kosma and D Lambrechts and {Le Marchand}, L and JM Li and A Lindblom and A Lophatananon and J Lubinski and A Mannermaa and S Manoukian and S Margolin and F Marme and K Matsuo and CA McLean and A Meindl and K Muir and SL Neuhausen and H Nevanlinna and S Nord and JE Olson and N Orr and P Peterlongo and TC Putti and A Rudolph and S Sangrajrang and EJ Sawyer and Schmidt, {MK (Marjanka)} and RK Schmutzler and CY Shen and JJ Shi and MJ Shrubsole and MC Southey and A Swerdlow and SH Teo and B Thienpont and AE Toland and RAEM Tollenaar and IPM Tomlinson and T Truong and CC Tseng and {van den Ouweland}, Ans and WQ Wen and R Winqvist and A Wu and CH Yip and MP Zamora and Y Zheng and P Hall and PDP Pharoah and J Simard and G Chenevix-Trench and AM Dunning and DF Easton and W Zheng",

year = "2015",

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

language = "Undefined/Unknown",

volume = "24",

pages = "1680--1691",

journal = "Cancer Epidemiology Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Guo, XY, Long, JR, Zeng, CJ, Michailidou, K, Ghoussaini, M, Bolla, MK, Wang, Q, Milne, RL, Shu, XO, Cai, QY, 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, Bruning, T, Burwinkel, B, Cai, H, Canisius, S, Chang-Claude, J, Choi, JY, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Droit, A, Dork, T, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Gaborieau, V, Garcia-Closas, M, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Hsiung, CN, Ito, H, Jakubowska, A, Johnson, N, Kabisch, M, Kang, D, Khan, S, Knight, JA, Kosma, VM, Lambrechts, D, Le Marchand, L, Li, JM, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McLean, CA, Meindl, A, Muir, K, Neuhausen, SL, Nevanlinna, H, Nord, S, Olson, JE, Orr, N, Peterlongo, P, Putti, TC, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shen, CY, Shi, JJ, Shrubsole, MJ, Southey, MC, Swerdlow, A, Teo, SH, Thienpont, B, Toland, AE, Tollenaar, RAEM, Tomlinson, IPM, Truong, T, Tseng, CC, van den Ouweland, A, Wen, WQ, Winqvist, R, Wu, A, Yip, CH, Zamora, MP, Zheng, Y, Hall, P, Pharoah, PDP, Simard, J, Chenevix-Trench, G, Dunning, AM, Easton, DF & Zheng, W 2015, 'Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk', Cancer Epidemiology Biomarkers & Prevention, vol. 24, no. 11, pp. 1680-1691. https://doi.org/10.1158/1055-9965.EPI-15-0363

TY - JOUR

T1 - Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

AU - Guo, XY

AU - Long, JR

AU - Zeng, CJ

AU - Michailidou, K

AU - Ghoussaini, M

AU - Bolla, MK

AU - Wang, Q (Qing)

AU - Milne, RL

AU - Shu, XO

AU - Cai, QY

AU - Beesley, J

AU - Kar, SP

AU - Andrulis, IL

AU - Anton-Culver, H

AU - Arndt, V

AU - Beckmann, MW

AU - Beeghly-Fadiel, A

AU - Benitez, J

AU - Blot, W

AU - Bogdanova, N

AU - Bojesen, SE

AU - Brauch, H

AU - Brenner, H

AU - Brinton, L

AU - Broeks, A

AU - Bruning, T

AU - Burwinkel, B

AU - Cai, H

AU - Canisius, S

AU - Chang-Claude, J

AU - Choi, JY

AU - Couch, FJ

AU - Cox, A

AU - Cross, SS

AU - Czene, K

AU - Darabi, H

AU - Devilee, P

AU - Droit, A

AU - Dork, T

AU - Fasching, PA

AU - Fletcher, O

AU - Flyger, H

AU - Fostira, F

AU - Gaborieau, V

AU - Garcia-Closas, M

AU - Giles, GG

AU - Grip, M

AU - Guenel, P

AU - Haiman, CA

AU - Hamann, U

AU - Hartman, M

AU - Hollestelle, Antoinette

AU - Hopper, JL

AU - Hsiung, CN

AU - Ito, H

AU - Jakubowska, A

AU - Johnson, N

AU - Kabisch, M

AU - Kang, D

AU - Khan, Salima

AU - Knight, JA

AU - Kosma, VM

AU - Lambrechts, D

AU - Le Marchand, L

AU - Li, JM

AU - Lindblom, A

AU - Lophatananon, A

AU - Lubinski, J

AU - Mannermaa, A

AU - Manoukian, S

AU - Margolin, S

AU - Marme, F

AU - Matsuo, K

AU - McLean, CA

AU - Meindl, A

AU - Muir, K

AU - Neuhausen, SL

AU - Nevanlinna, H

AU - Nord, S

AU - Olson, JE

AU - Orr, N

AU - Peterlongo, P

AU - Putti, TC

AU - Rudolph, A

AU - Sangrajrang, S

AU - Sawyer, EJ

AU - Schmidt, MK (Marjanka)

AU - Schmutzler, RK

AU - Shen, CY

AU - Shi, JJ

AU - Shrubsole, MJ

AU - Southey, MC

AU - Swerdlow, A

AU - Teo, SH

AU - Thienpont, B

AU - Toland, AE

AU - Tollenaar, RAEM

AU - Tomlinson, IPM

AU - Truong, T

AU - Tseng, CC

AU - van den Ouweland, Ans

AU - Wen, WQ

AU - Winqvist, R

AU - Wu, A

AU - Yip, CH

AU - Zamora, MP

AU - Zheng, Y

AU - Hall, P

AU - Pharoah, PDP

AU - Simard, J

AU - Chenevix-Trench, G

AU - Dunning, AM

AU - Easton, DF

AU - Zheng, W

PY - 2015

Y1 - 2015

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 x 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 x 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. (C) 2015 AACR.

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 x 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 x 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. (C) 2015 AACR.

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

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

M3 - Article

C2 - 26354892

SN - 1055-9965

VL - 24

SP - 1680

EP - 1691

JO - Cancer Epidemiology Biomarkers & Prevention

JF - Cancer Epidemiology Biomarkers & Prevention

IS - 11

ER -