Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

AM Mulligan; FJ Couch; D Barrowdale; SM Domchek; D Eccles; H Nevanlinna; SJ Ramus; M Robson; M Sherman; AB Spurdle; B Wappenschmidt; A Lee; L McGuffog; S Healey; OM Sinilnikova; R Janavicius; TV Hansen; FC Nielsen; B Ejlertsen; A Osorio; I Munoz-Repeto; M (Mercedes) Duran; J Godino; M Pertesi; J Benitez; P Peterlongo; S Manoukian; B Peissel; D Zaffaroni; E Cattaneo; B Bonanni; A Viel; B pasini; L Papi; L Ottini; A Savarese; L Bernard; P Radice; U Hamann; M Verheus; HEJ Meijers-Heijboer; J (Juul) van Wijnen; EBG Garcia; MR Nelen; CM Kets; Caroline Seynaeve; Madeleine Tilanus - Linthorst; RB van der Luijt; T Van Os; M Rookus; D Frost; JL Jones; DG Evans; F Lalloo; R Eeles; L Izatt; J Adlard; R Davidson; J Cook; A Donaldson; H Dorkins; H Gregory; J Eason; C Houghton; J Barwell; LE Side; E McCann; A Murray; S Peock; AK Godwin; RK Schmutzler; K Rhiem; C Engel; A Meindl; I Ruehl; N Arnold; D Niederacher; C Sutter; H Deissler; D Gadzicki; K Kast; S Preisler-Adams; R Varon-Mateeva; I Schoenbuchner; B Fiebig; W Heinritz; D Schafer; H Gevensleben; V Caux-Moncoutier; M Fassy-Colcombet; F Cornelis; S Mazoyer; M Leone; N Boutry-Kryza; A Hardouin; P Berthet; D Muller; JP Fricker; I Mortemousque; P Pujol; I Coupier; M Lebrun; C Kientz; M Longy; N Sevenet; D Stoppa-Lyonnet; C Isaacs; T Caldes; M de la Hoya; T Heikkinen; K Aittomaki; I Blanco; C (Conxi) Lazaro; RB Barkardottir; P Soucy; M Dumont; J Simard; M Montagna; S Tognazzo; E D'Andrea; S Fox; M Yan; T Rebbeck; OI Olopade; JN Weitzel; HT Lynch; PA Ganz; GE Tomlinson; XS Wang; Z Fredericksen; VS Pankratz; NM Lindor; C Szabo; K Offit; R Sakr; M Gaudet; J Bhatia; N Kauff; CF Singer; MK Tea; D Gschwantler-Kaulich; A Fink-Retter; PL Mai; MH Greene; E Imyanitov; FP O'Malley; H Ozcelik; G Glendon; AE Toland; AM Gerdes; Marga Thomassen; TA Kruse; UB Jensen; AB Skytte; MA Caligo; M Soller; K Henriksson; V Wachenfeldt; B Arver; M Stenmark-Askmalm; P Karlsson; YC Ding; SL Neuhausen; M Beattie; PDP Pharoah; KB Moysich; KL Nathanson; BY Karlan; J Gross; EM John; MB Daly; SM Buys; MC Southey; JL Hopper; MB Terry; W Chung; AF Miron; D Goldgar; G Chenevix-Trench; DF Easton; IL Andrulis; AC Antoniou

doi:10.1186/bcr3052

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

AM Mulligan, FJ Couch, D Barrowdale, SM Domchek, D Eccles, H Nevanlinna, SJ Ramus, M Robson, M Sherman, AB Spurdle, B Wappenschmidt, A Lee, L McGuffog, S Healey, OM Sinilnikova, R Janavicius, TV Hansen, FC Nielsen, B Ejlertsen, A OsorioI Munoz-Repeto, M (Mercedes) Duran, J Godino, M Pertesi, J Benitez, P Peterlongo, S Manoukian, B Peissel, D Zaffaroni, E Cattaneo, B Bonanni, A Viel, B pasini, L Papi, L Ottini, A Savarese, L Bernard, P Radice, U Hamann, M Verheus, HEJ Meijers-Heijboer, J (Juul) van Wijnen, EBG Garcia, MR Nelen, CM Kets, Caroline Seynaeve, Madeleine Tilanus - Linthorst, RB van der Luijt, T Van Os, M Rookus, D Frost, JL Jones, DG Evans, F Lalloo, R Eeles, L Izatt, J Adlard, R Davidson, J Cook, A Donaldson, H Dorkins, H Gregory, J Eason, C Houghton, J Barwell, LE Side, E McCann, A Murray, S Peock, AK Godwin, RK Schmutzler, K Rhiem, C Engel, A Meindl, I Ruehl, N Arnold, D Niederacher, C Sutter, H Deissler, D Gadzicki, K Kast, S Preisler-Adams, R Varon-Mateeva, I Schoenbuchner, B Fiebig, W Heinritz, D Schafer, H Gevensleben, V Caux-Moncoutier, M Fassy-Colcombet, F Cornelis, S Mazoyer, M Leone, N Boutry-Kryza, A Hardouin, P Berthet, D Muller, JP Fricker, I Mortemousque, P Pujol, I Coupier, M Lebrun, C Kientz, M Longy, N Sevenet, D Stoppa-Lyonnet, C Isaacs, T Caldes, M de la Hoya, T Heikkinen, K Aittomaki, I Blanco, C (Conxi) Lazaro, RB Barkardottir, P Soucy, M Dumont, J Simard, M Montagna, S Tognazzo, E D'Andrea, S Fox, M Yan, T Rebbeck, OI Olopade, JN Weitzel, HT Lynch, PA Ganz, GE Tomlinson, XS Wang, Z Fredericksen, VS Pankratz, NM Lindor, C Szabo, K Offit, R Sakr, M Gaudet, J Bhatia, N Kauff, CF Singer, MK Tea, D Gschwantler-Kaulich, A Fink-Retter, PL Mai, MH Greene, E Imyanitov, FP O'Malley, H Ozcelik, G Glendon, AE Toland, AM Gerdes, Marga Thomassen, TA Kruse, UB Jensen, AB Skytte, MA Caligo, M Soller, K Henriksson, V Wachenfeldt, B Arver, M Stenmark-Askmalm, P Karlsson, YC Ding, SL Neuhausen, M Beattie, PDP Pharoah, KB Moysich, KL Nathanson, BY Karlan, J Gross, EM John, MB Daly, SM Buys, MC Southey, JL Hopper, MB Terry, W Chung, AF Miron, D Goldgar, G Chenevix-Trench, DF Easton, IL Andrulis, AC Antoniou

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Abstract

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Original language	Undefined/Unknown
Journal	Breast Cancer Research
Volume	13
Issue number	6
DOIs	https://doi.org/10.1186/bcr3052
Publication status	Published - 2011

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Mulligan, AM., Couch, FJ., Barrowdale, D., Domchek, SM., Eccles, D., Nevanlinna, H., Ramus, SJ., Robson, M., Sherman, M., Spurdle, AB., Wappenschmidt, B., Lee, A., McGuffog, L., Healey, S., Sinilnikova, OM., Janavicius, R., Hansen, TV., Nielsen, FC., Ejlertsen, B., ... Antoniou, AC. (2011). Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Research, 13(6). https://doi.org/10.1186/bcr3052

@article{10fc6a5d1217407db5646cccb32a2439,

title = "Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2",

abstract = "Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.",

author = "AM Mulligan and FJ Couch and D Barrowdale and SM Domchek and D Eccles and H Nevanlinna and SJ Ramus and M Robson and M Sherman and AB Spurdle and B Wappenschmidt and A Lee and L McGuffog and S Healey and OM Sinilnikova and R Janavicius and TV Hansen and FC Nielsen and B Ejlertsen and A Osorio and I Munoz-Repeto and Duran, {M (Mercedes)} and J Godino and M Pertesi and J Benitez and P Peterlongo and S Manoukian and B Peissel and D Zaffaroni and E Cattaneo and B Bonanni and A Viel and B pasini and L Papi and L Ottini and A Savarese and L Bernard and P Radice and U Hamann and M Verheus and HEJ Meijers-Heijboer and {van Wijnen}, {J (Juul)} and EBG Garcia and MR Nelen and CM Kets and Caroline Seynaeve and {Tilanus - Linthorst}, Madeleine and {van der Luijt}, RB and {Van Os}, T and M Rookus and D Frost and JL Jones and DG Evans and F Lalloo and R Eeles and L Izatt and J Adlard and R Davidson and J Cook and A Donaldson and H Dorkins and H Gregory and J Eason and C Houghton and J Barwell and LE Side and E McCann and A Murray and S Peock and AK Godwin and RK Schmutzler and K Rhiem and C Engel and A Meindl and I Ruehl and N Arnold and D Niederacher and C Sutter and H Deissler and D Gadzicki and K Kast and S Preisler-Adams and R Varon-Mateeva and I Schoenbuchner and B Fiebig and W Heinritz and D Schafer and H Gevensleben and V Caux-Moncoutier and M Fassy-Colcombet and F Cornelis and S Mazoyer and M Leone and N Boutry-Kryza and A Hardouin and P Berthet and D Muller and JP Fricker and I Mortemousque and P Pujol and I Coupier and M Lebrun and C Kientz and M Longy and N Sevenet and D Stoppa-Lyonnet and C Isaacs and T Caldes and {de la Hoya}, M and T Heikkinen and K Aittomaki and I Blanco and Lazaro, {C (Conxi)} and RB Barkardottir and P Soucy and M Dumont and J Simard and M Montagna and S Tognazzo and E D'Andrea and S Fox and M Yan and T Rebbeck and OI Olopade and JN Weitzel and HT Lynch and PA Ganz and GE Tomlinson and XS Wang and Z Fredericksen and VS Pankratz and NM Lindor and C Szabo and K Offit and R Sakr and M Gaudet and J Bhatia and N Kauff and CF Singer and MK Tea and D Gschwantler-Kaulich and A Fink-Retter and PL Mai and MH Greene and E Imyanitov and FP O'Malley and H Ozcelik and G Glendon and AE Toland and AM Gerdes and Marga Thomassen and TA Kruse and UB Jensen and AB Skytte and MA Caligo and M Soller and K Henriksson and V Wachenfeldt and B Arver and M Stenmark-Askmalm and P Karlsson and YC Ding and SL Neuhausen and M Beattie and PDP Pharoah and KB Moysich and KL Nathanson and BY Karlan and J Gross and EM John and MB Daly and SM Buys and MC Southey and JL Hopper and MB Terry and W Chung and AF Miron and D Goldgar and G Chenevix-Trench and DF Easton and IL Andrulis and AC Antoniou",

year = "2011",

doi = "10.1186/bcr3052",

language = "Undefined/Unknown",

volume = "13",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "6",

}

Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TV, Nielsen, FC, Ejlertsen, B, Osorio, A, Munoz-Repeto, I, Duran, M, Godino, J, Pertesi, M, Benitez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, van Wijnen, J, Garcia, EBG, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus - Linthorst, M, van der Luijt, RB, Van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schafer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Leone, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, JP, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomaki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, OI, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, XS, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, MK, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, AM, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, AB, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, V, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL & Antoniou, AC 2011, 'Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2', Breast Cancer Research, vol. 13, no. 6. https://doi.org/10.1186/bcr3052

TY - JOUR

T1 - Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

AU - Mulligan, AM

AU - Couch, FJ

AU - Barrowdale, D

AU - Domchek, SM

AU - Eccles, D

AU - Nevanlinna, H

AU - Ramus, SJ

AU - Robson, M

AU - Sherman, M

AU - Spurdle, AB

AU - Wappenschmidt, B

AU - Lee, A

AU - McGuffog, L

AU - Healey, S

AU - Sinilnikova, OM

AU - Janavicius, R

AU - Hansen, TV

AU - Nielsen, FC

AU - Ejlertsen, B

AU - Osorio, A

AU - Munoz-Repeto, I

AU - Duran, M (Mercedes)

AU - Godino, J

AU - Pertesi, M

AU - Benitez, J

AU - Peterlongo, P

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Cattaneo, E

AU - Bonanni, B

AU - Viel, A

AU - pasini, B

AU - Papi, L

AU - Ottini, L

AU - Savarese, A

AU - Bernard, L

AU - Radice, P

AU - Hamann, U

AU - Verheus, M

AU - Meijers-Heijboer, HEJ

AU - van Wijnen, J (Juul)

AU - Garcia, EBG

AU - Nelen, MR

AU - Kets, CM

AU - Seynaeve, Caroline

AU - Tilanus - Linthorst, Madeleine

AU - van der Luijt, RB

AU - Van Os, T

AU - Rookus, M

AU - Frost, D

AU - Jones, JL

AU - Evans, DG

AU - Lalloo, F

AU - Eeles, R

AU - Izatt, L

AU - Adlard, J

AU - Davidson, R

AU - Cook, J

AU - Donaldson, A

AU - Dorkins, H

AU - Gregory, H

AU - Eason, J

AU - Houghton, C

AU - Barwell, J

AU - Side, LE

AU - McCann, E

AU - Murray, A

AU - Peock, S

AU - Godwin, AK

AU - Schmutzler, RK

AU - Rhiem, K

AU - Engel, C

AU - Meindl, A

AU - Ruehl, I

AU - Arnold, N

AU - Niederacher, D

AU - Sutter, C

AU - Deissler, H

AU - Gadzicki, D

AU - Kast, K

AU - Preisler-Adams, S

AU - Varon-Mateeva, R

AU - Schoenbuchner, I

AU - Fiebig, B

AU - Heinritz, W

AU - Schafer, D

AU - Gevensleben, H

AU - Caux-Moncoutier, V

AU - Fassy-Colcombet, M

AU - Cornelis, F

AU - Mazoyer, S

AU - Leone, M

AU - Boutry-Kryza, N

AU - Hardouin, A

AU - Berthet, P

AU - Muller, D

AU - Fricker, JP

AU - Mortemousque, I

AU - Pujol, P

AU - Coupier, I

AU - Lebrun, M

AU - Kientz, C

AU - Longy, M

AU - Sevenet, N

AU - Stoppa-Lyonnet, D

AU - Isaacs, C

AU - Caldes, T

AU - de la Hoya, M

AU - Heikkinen, T

AU - Aittomaki, K

AU - Blanco, I

AU - Lazaro, C (Conxi)

AU - Barkardottir, RB

AU - Soucy, P

AU - Dumont, M

AU - Simard, J

AU - Montagna, M

AU - Tognazzo, S

AU - D'Andrea, E

AU - Fox, S

AU - Yan, M

AU - Rebbeck, T

AU - Olopade, OI

AU - Weitzel, JN

AU - Lynch, HT

AU - Ganz, PA

AU - Tomlinson, GE

AU - Wang, XS

AU - Fredericksen, Z

AU - Pankratz, VS

AU - Lindor, NM

AU - Szabo, C

AU - Offit, K

AU - Sakr, R

AU - Gaudet, M

AU - Bhatia, J

AU - Kauff, N

AU - Singer, CF

AU - Tea, MK

AU - Gschwantler-Kaulich, D

AU - Fink-Retter, A

AU - Mai, PL

AU - Greene, MH

AU - Imyanitov, E

AU - O'Malley, FP

AU - Ozcelik, H

AU - Glendon, G

AU - Toland, AE

AU - Gerdes, AM

AU - Thomassen, Marga

AU - Kruse, TA

AU - Jensen, UB

AU - Skytte, AB

AU - Caligo, MA

AU - Soller, M

AU - Henriksson, K

AU - Wachenfeldt, V

AU - Arver, B

AU - Stenmark-Askmalm, M

AU - Karlsson, P

AU - Ding, YC

AU - Neuhausen, SL

AU - Beattie, M

AU - Pharoah, PDP

AU - Moysich, KB

AU - Nathanson, KL

AU - Karlan, BY

AU - Gross, J

AU - John, EM

AU - Daly, MB

AU - Buys, SM

AU - Southey, MC

AU - Hopper, JL

AU - Terry, MB

AU - Chung, W

AU - Miron, AF

AU - Goldgar, D

AU - Chenevix-Trench, G

AU - Easton, DF

AU - Andrulis, IL

AU - Antoniou, AC

PY - 2011

Y1 - 2011

N2 - Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

AB - Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

U2 - 10.1186/bcr3052

DO - 10.1186/bcr3052

M3 - Article

C2 - 22053997

SN - 1465-5411

VL - 13

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 6

ER -