Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

AC Antoniou; C Kartsonaki; OM Sinilnikova; P Soucy; L McGuffog; S Healey; A Lee; P Peterlongo; S Manoukian; B Peissel; D Zaffaroni; E Cattaneo; M Barile; V Pensotti; B pasini; R Dolcetti; G Giannini; AL Putignano; L Varesco; P Radice; PL Mai; MH Greene; IL Andrulis; G Glendon; H Ozcelik; Marga Thomassen; AM Gerdes; TA Kruse; UB Jensen; DG Cruger; MA Caligo; Y Laitman; R Milgrom; B Kaufman; S Paluch-Shimon; E Friedman; N Loman; K Harbst; A Lindblom; B Arver; H Ehrencrona; B Melin; KL Nathanson; SM Domchek; T Rebbeck; A Jakubowska; J Lubinski; J Gronwald; T Huzarski; T Byrski; C Cybulski; B Gorski; A Osorio; TRY Cajal; F Fostira; R Andres; J Benitez; U Hamann; FB Hogervorst; MA Rookus; Maartje Hooning; MR Nelen; RB van der Luijt; TAM van Os; CJ van Asperen; P Devilee; HEJ Meijers-Heijboer; EBG Garcia; S Peock; M Cook; D Frost; R Platte; J Leyland; DG Evans; F Lalloo; R Eeles; L Izatt; J Adlard; R Davidson; D Eccles; KR Ong; J Cook; F Douglas; J Paterson; MJ Kennedy; Z Miedzybrodzka; A Godwin; D Stoppa-Lyonnet; B Buecher; M Belotti; C Tirapo; S Mazoyer; L Barjhoux; C Lasset; D Leroux; L Faivre; M Bronner; F Prieur; C Nogues; E Rouleau; P Pujol; I Coupier; M Frenay; JL Hopper; MB Daly; MB Terry; EM John; SS Buys; Y Yassin; A Miron; D Goldgar; CF Singer; MK Tea; G Pfeiler; AC Dressler; TV Hansen; L Jonson; B Ejlertsen; RB Barkardottir; T Kirchhoff; K Offit; M Piedmonte; G Rodriguez; L Small; J Boggess; S Blank; J Basil; M Azodi; AE Toland; M Montagna; S Tognazzo; S Agata; E Imyanitov; R Janavicius; C (Conxi) Lazaro; I Blanco; PDP Pharoah; L Sucheston; BY Karlan; CS Walsh; E Olah; A Bozsik; SH Teo; JL Seldon; MS Beattie; EJ van Rensburg; MD Sluiter; O Diez; RK Schmutzler; B Wappenschmidt; C Engel; A Meindl; I Ruehl; R Varon-Mateeva; K Kast; H Deissler; D Niederacher; N Arnold; D Gadzicki; I Schonbuchner; T Caldes; M de la Hoya; H Nevanlinna; K Aittomaki; M Dumont; J Chiquette; M Tischkowitz; XQ Chen; J Beesley; AB Spurdle; SL Neuhausen; YC Ding; Z Fredericksen; X Wang; VS Pankratz; F Couch; J Simard; DF Easton; G Chenevix-Trench

doi:10.1093/hmg/ddr226

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

AC Antoniou, C Kartsonaki, OM Sinilnikova, P Soucy, L McGuffog, S Healey, A Lee, P Peterlongo, S Manoukian, B Peissel, D Zaffaroni, E Cattaneo, M Barile, V Pensotti, B pasini, R Dolcetti, G Giannini, AL Putignano, L Varesco, P RadicePL Mai, MH Greene, IL Andrulis, G Glendon, H Ozcelik, Marga Thomassen, AM Gerdes, TA Kruse, UB Jensen, DG Cruger, MA Caligo, Y Laitman, R Milgrom, B Kaufman, S Paluch-Shimon, E Friedman, N Loman, K Harbst, A Lindblom, B Arver, H Ehrencrona, B Melin, KL Nathanson, SM Domchek, T Rebbeck, A Jakubowska, J Lubinski, J Gronwald, T Huzarski, T Byrski, C Cybulski, B Gorski, A Osorio, TRY Cajal, F Fostira, R Andres, J Benitez, U Hamann, FB Hogervorst, MA Rookus, Maartje Hooning, MR Nelen, RB van der Luijt, TAM van Os, CJ van Asperen, P Devilee, HEJ Meijers-Heijboer, EBG Garcia, S Peock, M Cook, D Frost, R Platte, J Leyland, DG Evans, F Lalloo, R Eeles, L Izatt, J Adlard, R Davidson, D Eccles, KR Ong, J Cook, F Douglas, J Paterson, MJ Kennedy, Z Miedzybrodzka, A Godwin, D Stoppa-Lyonnet, B Buecher, M Belotti, C Tirapo, S Mazoyer, L Barjhoux, C Lasset, D Leroux, L Faivre, M Bronner, F Prieur, C Nogues, E Rouleau, P Pujol, I Coupier, M Frenay, JL Hopper, MB Daly, MB Terry, EM John, SS Buys, Y Yassin, A Miron, D Goldgar, CF Singer, MK Tea, G Pfeiler, AC Dressler, TV Hansen, L Jonson, B Ejlertsen, RB Barkardottir, T Kirchhoff, K Offit, M Piedmonte, G Rodriguez, L Small, J Boggess, S Blank, J Basil, M Azodi, AE Toland, M Montagna, S Tognazzo, S Agata, E Imyanitov, R Janavicius, C (Conxi) Lazaro, I Blanco, PDP Pharoah, L Sucheston, BY Karlan, CS Walsh, E Olah, A Bozsik, SH Teo, JL Seldon, MS Beattie, EJ van Rensburg, MD Sluiter, O Diez, RK Schmutzler, B Wappenschmidt, C Engel, A Meindl, I Ruehl, R Varon-Mateeva, K Kast, H Deissler, D Niederacher, N Arnold, D Gadzicki, I Schonbuchner, T Caldes, M de la Hoya, H Nevanlinna, K Aittomaki, M Dumont, J Chiquette, M Tischkowitz, XQ Chen, J Beesley, AB Spurdle, SL Neuhausen, YC Ding, Z Fredericksen, X Wang, VS Pankratz, F Couch, J Simard, DF Easton, G Chenevix-Trench

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

60 Citations (Scopus)

Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Original language	Undefined/Unknown
Pages (from-to)	3304-3321
Number of pages	18
Journal	Human Molecular Genetics
Volume	20
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddr226
Publication status	Published - 2011

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EMC MM-03-86-01

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Access to Document

10.1093/hmg/ddr226

http://hdl.handle.net/1765/34038

Cite this

Antoniou, AC., Kartsonaki, C., Sinilnikova, OM., Soucy, P., McGuffog, L., Healey, S., Lee, A., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Barile, M., Pensotti, V., pasini, B., Dolcetti, R., Giannini, G., Putignano, AL., Varesco, L., ... Chenevix-Trench, G. (2011). Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics, 20(16), 3304-3321. https://doi.org/10.1093/hmg/ddr226

@article{0c9a4edd6a334541b9aa7083362b2bb6,

title = "Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers",

abstract = "Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.",

author = "AC Antoniou and C Kartsonaki and OM Sinilnikova and P Soucy and L McGuffog and S Healey and A Lee and P Peterlongo and S Manoukian and B Peissel and D Zaffaroni and E Cattaneo and M Barile and V Pensotti and B pasini and R Dolcetti and G Giannini and AL Putignano and L Varesco and P Radice and PL Mai and MH Greene and IL Andrulis and G Glendon and H Ozcelik and Marga Thomassen and AM Gerdes and TA Kruse and UB Jensen and DG Cruger and MA Caligo and Y Laitman and R Milgrom and B Kaufman and S Paluch-Shimon and E Friedman and N Loman and K Harbst and A Lindblom and B Arver and H Ehrencrona and B Melin and KL Nathanson and SM Domchek and T Rebbeck and A Jakubowska and J Lubinski and J Gronwald and T Huzarski and T Byrski and C Cybulski and B Gorski and A Osorio and TRY Cajal and F Fostira and R Andres and J Benitez and U Hamann and FB Hogervorst and MA Rookus and Maartje Hooning and MR Nelen and {van der Luijt}, RB and {van Os}, TAM and {van Asperen}, CJ and P Devilee and HEJ Meijers-Heijboer and EBG Garcia and S Peock and M Cook and D Frost and R Platte and J Leyland and DG Evans and F Lalloo and R Eeles and L Izatt and J Adlard and R Davidson and D Eccles and KR Ong and J Cook and F Douglas and J Paterson and MJ Kennedy and Z Miedzybrodzka and A Godwin and D Stoppa-Lyonnet and B Buecher and M Belotti and C Tirapo and S Mazoyer and L Barjhoux and C Lasset and D Leroux and L Faivre and M Bronner and F Prieur and C Nogues and E Rouleau and P Pujol and I Coupier and M Frenay and JL Hopper and MB Daly and MB Terry and EM John and SS Buys and Y Yassin and A Miron and D Goldgar and CF Singer and MK Tea and G Pfeiler and AC Dressler and TV Hansen and L Jonson and B Ejlertsen and RB Barkardottir and T Kirchhoff and K Offit and M Piedmonte and G Rodriguez and L Small and J Boggess and S Blank and J Basil and M Azodi and AE Toland and M Montagna and S Tognazzo and S Agata and E Imyanitov and R Janavicius and Lazaro, {C (Conxi)} and I Blanco and PDP Pharoah and L Sucheston and BY Karlan and CS Walsh and E Olah and A Bozsik and SH Teo and JL Seldon and MS Beattie and {van Rensburg}, EJ and MD Sluiter and O Diez and RK Schmutzler and B Wappenschmidt and C Engel and A Meindl and I Ruehl and R Varon-Mateeva and K Kast and H Deissler and D Niederacher and N Arnold and D Gadzicki and I Schonbuchner and T Caldes and {de la Hoya}, M and H Nevanlinna and K Aittomaki and M Dumont and J Chiquette and M Tischkowitz and XQ Chen and J Beesley and AB Spurdle and SL Neuhausen and YC Ding and Z Fredericksen and X Wang and VS Pankratz and F Couch and J Simard and DF Easton and G Chenevix-Trench",

year = "2011",

doi = "10.1093/hmg/ddr226",

language = "Undefined/Unknown",

volume = "20",

pages = "3304--3321",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

Antoniou, AC, Kartsonaki, C, Sinilnikova, OM, Soucy, P, McGuffog, L, Healey, S, Lee, A, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Barile, M, Pensotti, V, pasini, B, Dolcetti, R, Giannini, G, Putignano, AL, Varesco, L, Radice, P, Mai, PL, Greene, MH, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, AM, Kruse, TA, Jensen, UB, Cruger, DG, Caligo, MA, Laitman, Y, Milgrom, R, Kaufman, B, Paluch-Shimon, S, Friedman, E, Loman, N, Harbst, K, Lindblom, A, Arver, B, Ehrencrona, H, Melin, B, Nathanson, KL, Domchek, SM, Rebbeck, T, Jakubowska, A, Lubinski, J, Gronwald, J, Huzarski, T, Byrski, T, Cybulski, C, Gorski, B, Osorio, A, Cajal, TRY, Fostira, F, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, Rookus, MA, Hooning, M, Nelen, MR, van der Luijt, RB, van Os, TAM, van Asperen, CJ, Devilee, P, Meijers-Heijboer, HEJ, Garcia, EBG, Peock, S, Cook, M, Frost, D, Platte, R, Leyland, J, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Eccles, D, Ong, KR, Cook, J, Douglas, F, Paterson, J, Kennedy, MJ, Miedzybrodzka, Z, Godwin, A, Stoppa-Lyonnet, D, Buecher, B, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Lasset, C, Leroux, D, Faivre, L, Bronner, M, Prieur, F, Nogues, C, Rouleau, E, Pujol, P, Coupier, I, Frenay, M, Hopper, JL, Daly, MB, Terry, MB, John, EM, Buys, SS, Yassin, Y, Miron, A, Goldgar, D, Singer, CF, Tea, MK, Pfeiler, G, Dressler, AC, Hansen, TV, Jonson, L, Ejlertsen, B, Barkardottir, RB, Kirchhoff, T, Offit, K, Piedmonte, M, Rodriguez, G, Small, L, Boggess, J, Blank, S, Basil, J, Azodi, M, Toland, AE, Montagna, M, Tognazzo, S, Agata, S, Imyanitov, E, Janavicius, R, Lazaro, C, Blanco, I, Pharoah, PDP, Sucheston, L, Karlan, BY, Walsh, CS, Olah, E, Bozsik, A, Teo, SH, Seldon, JL, Beattie, MS, van Rensburg, EJ, Sluiter, MD, Diez, O, Schmutzler, RK, Wappenschmidt, B, Engel, C, Meindl, A, Ruehl, I, Varon-Mateeva, R, Kast, K, Deissler, H, Niederacher, D, Arnold, N, Gadzicki, D, Schonbuchner, I, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomaki, K, Dumont, M, Chiquette, J, Tischkowitz, M, Chen, XQ, Beesley, J, Spurdle, AB, Neuhausen, SL, Ding, YC, Fredericksen, Z, Wang, X, Pankratz, VS, Couch, F, Simard, J, Easton, DF & Chenevix-Trench, G 2011, 'Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers', Human Molecular Genetics, vol. 20, no. 16, pp. 3304-3321. https://doi.org/10.1093/hmg/ddr226

TY - JOUR

T1 - Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

AU - Antoniou, AC

AU - Kartsonaki, C

AU - Sinilnikova, OM

AU - Soucy, P

AU - McGuffog, L

AU - Healey, S

AU - Lee, A

AU - Peterlongo, P

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Cattaneo, E

AU - Barile, M

AU - Pensotti, V

AU - pasini, B

AU - Dolcetti, R

AU - Giannini, G

AU - Putignano, AL

AU - Varesco, L

AU - Radice, P

AU - Mai, PL

AU - Greene, MH

AU - Andrulis, IL

AU - Glendon, G

AU - Ozcelik, H

AU - Thomassen, Marga

AU - Gerdes, AM

AU - Kruse, TA

AU - Jensen, UB

AU - Cruger, DG

AU - Caligo, MA

AU - Laitman, Y

AU - Milgrom, R

AU - Kaufman, B

AU - Paluch-Shimon, S

AU - Friedman, E

AU - Loman, N

AU - Harbst, K

AU - Lindblom, A

AU - Arver, B

AU - Ehrencrona, H

AU - Melin, B

AU - Nathanson, KL

AU - Domchek, SM

AU - Rebbeck, T

AU - Jakubowska, A

AU - Lubinski, J

AU - Gronwald, J

AU - Huzarski, T

AU - Byrski, T

AU - Cybulski, C

AU - Gorski, B

AU - Osorio, A

AU - Cajal, TRY

AU - Fostira, F

AU - Andres, R

AU - Benitez, J

AU - Hamann, U

AU - Hogervorst, FB

AU - Rookus, MA

AU - Hooning, Maartje

AU - Nelen, MR

AU - van der Luijt, RB

AU - van Os, TAM

AU - van Asperen, CJ

AU - Devilee, P

AU - Meijers-Heijboer, HEJ

AU - Garcia, EBG

AU - Peock, S

AU - Cook, M

AU - Frost, D

AU - Platte, R

AU - Leyland, J

AU - Evans, DG

AU - Lalloo, F

AU - Eeles, R

AU - Izatt, L

AU - Adlard, J

AU - Davidson, R

AU - Eccles, D

AU - Ong, KR

AU - Cook, J

AU - Douglas, F

AU - Paterson, J

AU - Kennedy, MJ

AU - Miedzybrodzka, Z

AU - Godwin, A

AU - Stoppa-Lyonnet, D

AU - Buecher, B

AU - Belotti, M

AU - Tirapo, C

AU - Mazoyer, S

AU - Barjhoux, L

AU - Lasset, C

AU - Leroux, D

AU - Faivre, L

AU - Bronner, M

AU - Prieur, F

AU - Nogues, C

AU - Rouleau, E

AU - Pujol, P

AU - Coupier, I

AU - Frenay, M

AU - Hopper, JL

AU - Daly, MB

AU - Terry, MB

AU - John, EM

AU - Buys, SS

AU - Yassin, Y

AU - Miron, A

AU - Goldgar, D

AU - Singer, CF

AU - Tea, MK

AU - Pfeiler, G

AU - Dressler, AC

AU - Hansen, TV

AU - Jonson, L

AU - Ejlertsen, B

AU - Barkardottir, RB

AU - Kirchhoff, T

AU - Offit, K

AU - Piedmonte, M

AU - Rodriguez, G

AU - Small, L

AU - Boggess, J

AU - Blank, S

AU - Basil, J

AU - Azodi, M

AU - Toland, AE

AU - Montagna, M

AU - Tognazzo, S

AU - Agata, S

AU - Imyanitov, E

AU - Janavicius, R

AU - Lazaro, C (Conxi)

AU - Blanco, I

AU - Pharoah, PDP

AU - Sucheston, L

AU - Karlan, BY

AU - Walsh, CS

AU - Olah, E

AU - Bozsik, A

AU - Teo, SH

AU - Seldon, JL

AU - Beattie, MS

AU - van Rensburg, EJ

AU - Sluiter, MD

AU - Diez, O

AU - Schmutzler, RK

AU - Wappenschmidt, B

AU - Engel, C

AU - Meindl, A

AU - Ruehl, I

AU - Varon-Mateeva, R

AU - Kast, K

AU - Deissler, H

AU - Niederacher, D

AU - Arnold, N

AU - Gadzicki, D

AU - Schonbuchner, I

AU - Caldes, T

AU - de la Hoya, M

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Dumont, M

AU - Chiquette, J

AU - Tischkowitz, M

AU - Chen, XQ

AU - Beesley, J

AU - Spurdle, AB

AU - Neuhausen, SL

AU - Ding, YC

AU - Fredericksen, Z

AU - Wang, X

AU - Pankratz, VS

AU - Couch, F

AU - Simard, J

AU - Easton, DF

AU - Chenevix-Trench, G

PY - 2011

Y1 - 2011

N2 - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

AB - Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

U2 - 10.1093/hmg/ddr226

DO - 10.1093/hmg/ddr226

M3 - Article

C2 - 21593217

SN - 0964-6906

VL - 20

SP - 3304

EP - 3321

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -