Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

AC Antoniou; J Beesley; L McGuffog; OM Sinilnikova; S Healey; SL Neuhausen; YC Ding; TR Rebbeck; JN Weitzel; HT Lynch; C Isaacs; PA Ganz; G Tomlinson; OI Olopade; FJ Couch; XS Wang; NM Lindor; VS Pankratz; P Radice; S Manoukian; B Peissel; D Zaffaroni; M Barile; A Viel; A Allavena; V Dall'Olio; P Peterlongo; CI Szabo; M Zikan; K Claes; B (Bruce) Poppe; L Foretova; PL Mai; MH Greene; G Rennert; F Lejbkowicz; G Glendon; H Ozcelik; IL Andrulis; Marga Thomassen; AM Gerdes; L Sunde; D Cruger; UB Jensen; M Caligo; E Friedman; B Kaufman; Y Laitman; R Milgrom; M Dubrovsky; S Cohen; A Borg; H Jernstrom; A Lindblom; J Rantala; M Stenmark-Askmalm; B Melin; K Nathanson; S Domchek; A Jakubowska; J Lubinski; T Huzarski; A Osorio; A Lasa; M (Mercedes) Duran; MI Tejada; J Godino; J Benitez; U Hamann; Mieke Kriege; N Hoogerbrugge; RB van der Luijt; CJ van Asperen; P Devilee; EJ Meijers-Heijboer; MJ Blok; CM Aalfs; F Hogervorst; M Rookus; M Cook; C Oliver; D Frost; D Conroy; DG Evans; F Lalloo; G Pichert; R Davidson; T Cole; J Cook; J Paterson; S Hodgson; PJ Morrison; ME Porteous; L Walker; MJ Kennedy; H Dorkins; S Peock; AK Godwin; D Stoppa-Lyonnet; A de Pauw; S Mazoyer; V Bonadona; C Lasset; H Dreyfus; D Leroux; A Hardouin; P Berthet; L Faivre; C Loustalot; T Noguchi; H Sobol; E Rouleau; C Nogues; M Frenay; L Venat-Bouvet; JL Hopper; MB Daly; MB Terry; EM John; SS Buys; Y Yassin; A Miron; D Goldgar; CF Singer; AC Dressler; D Gschwantler-Kaulich; G Pfeiler; TVO Hansen; L Jnson; BA Agnarsson; T Kirchhoff; K Offit; V Devlin; A Dutra-Clarke; M Piedmonte; GC Rodriguez; K Wakeley; JF Boggess; J Basil; PE Schwartz; SV Blank; AE Toland; M Montagna; C Casella; E Imyanitov; L Tihomirova; I Blanco; C (Conxi) Lazaro; SJ Ramus; L Sucheston; BY Karlan; J Gross; R Schmutzler; B Wappenschmidt; C Engel; A Meindl; M Lochmann; N Arnold; S Heidemann; R Varon-Mateeva; D Niederacher; C Sutter; H Deissler; D Gadzicki; S Preisler-Adams; K Kast; I Schonbuchner; T Caldes; M de la Hoya; K Aittomaki; H Nevanlinna; J Simard; AB Spurdle; H Holland; XQ Chen; R Platte; G Chenevix-Trench; DF Easton

doi:10.1158/0008-5472.CAN-10-1907

Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

AC Antoniou, J Beesley, L McGuffog, OM Sinilnikova, S Healey, SL Neuhausen, YC Ding, TR Rebbeck, JN Weitzel, HT Lynch, C Isaacs, PA Ganz, G Tomlinson, OI Olopade, FJ Couch, XS Wang, NM Lindor, VS Pankratz, P Radice, S ManoukianB Peissel, D Zaffaroni, M Barile, A Viel, A Allavena, V Dall'Olio, P Peterlongo, CI Szabo, M Zikan, K Claes, B (Bruce) Poppe, L Foretova, PL Mai, MH Greene, G Rennert, F Lejbkowicz, G Glendon, H Ozcelik, IL Andrulis, Marga Thomassen, AM Gerdes, L Sunde, D Cruger, UB Jensen, M Caligo, E Friedman, B Kaufman, Y Laitman, R Milgrom, M Dubrovsky, S Cohen, A Borg, H Jernstrom, A Lindblom, J Rantala, M Stenmark-Askmalm, B Melin, K Nathanson, S Domchek, A Jakubowska, J Lubinski, T Huzarski, A Osorio, A Lasa, M (Mercedes) Duran, MI Tejada, J Godino, J Benitez, U Hamann, Mieke Kriege, N Hoogerbrugge, RB van der Luijt, CJ van Asperen, P Devilee, EJ Meijers-Heijboer, MJ Blok, CM Aalfs, F Hogervorst, M Rookus, M Cook, C Oliver, D Frost, D Conroy, DG Evans, F Lalloo, G Pichert, R Davidson, T Cole, J Cook, J Paterson, S Hodgson, PJ Morrison, ME Porteous, L Walker, MJ Kennedy, H Dorkins, S Peock, AK Godwin, D Stoppa-Lyonnet, A de Pauw, S Mazoyer, V Bonadona, C Lasset, H Dreyfus, D Leroux, A Hardouin, P Berthet, L Faivre, C Loustalot, T Noguchi, H Sobol, E Rouleau, C Nogues, M Frenay, L Venat-Bouvet, JL Hopper, MB Daly, MB Terry, EM John, SS Buys, Y Yassin, A Miron, D Goldgar, CF Singer, AC Dressler, D Gschwantler-Kaulich, G Pfeiler, TVO Hansen, L Jnson, BA Agnarsson, T Kirchhoff, K Offit, V Devlin, A Dutra-Clarke, M Piedmonte, GC Rodriguez, K Wakeley, JF Boggess, J Basil, PE Schwartz, SV Blank, AE Toland, M Montagna, C Casella, E Imyanitov, L Tihomirova, I Blanco, C (Conxi) Lazaro, SJ Ramus, L Sucheston, BY Karlan, J Gross, R Schmutzler, B Wappenschmidt, C Engel, A Meindl, M Lochmann, N Arnold, S Heidemann, R Varon-Mateeva, D Niederacher, C Sutter, H Deissler, D Gadzicki, S Preisler-Adams, K Kast, I Schonbuchner, T Caldes, M de la Hoya, K Aittomaki, H Nevanlinna, J Simard, AB Spurdle, H Holland, XQ Chen, R Platte, G Chenevix-Trench, DF Easton

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

160 Citations (Scopus)

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42%

Original language	Undefined/Unknown
Pages (from-to)	9742-9754
Number of pages	13
Journal	Cancer Research
Volume	70
Issue number	23
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-1907
Publication status	Published - 2010

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10.1158/0008-5472.CAN-10-1907

http://hdl.handle.net/1765/27432

Cite this

Antoniou, AC., Beesley, J., McGuffog, L., Sinilnikova, OM., Healey, S., Neuhausen, SL., Ding, YC., Rebbeck, TR., Weitzel, JN., Lynch, HT., Isaacs, C., Ganz, PA., Tomlinson, G., Olopade, OI., Couch, FJ., Wang, XS., Lindor, NM., Pankratz, VS., Radice, P., ... Easton, DF. (2010). Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction. Cancer Research, 70(23), 9742-9754. https://doi.org/10.1158/0008-5472.CAN-10-1907

@article{1ffa0aca822d4ef9a8bca5c012113ba0,

title = "Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction",

abstract = "The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42%",

author = "AC Antoniou and J Beesley and L McGuffog and OM Sinilnikova and S Healey and SL Neuhausen and YC Ding and TR Rebbeck and JN Weitzel and HT Lynch and C Isaacs and PA Ganz and G Tomlinson and OI Olopade and FJ Couch and XS Wang and NM Lindor and VS Pankratz and P Radice and S Manoukian and B Peissel and D Zaffaroni and M Barile and A Viel and A Allavena and V Dall'Olio and P Peterlongo and CI Szabo and M Zikan and K Claes and Poppe, {B (Bruce)} and L Foretova and PL Mai and MH Greene and G Rennert and F Lejbkowicz and G Glendon and H Ozcelik and IL Andrulis and Marga Thomassen and AM Gerdes and L Sunde and D Cruger and UB Jensen and M Caligo and E Friedman and B Kaufman and Y Laitman and R Milgrom and M Dubrovsky and S Cohen and A Borg and H Jernstrom and A Lindblom and J Rantala and M Stenmark-Askmalm and B Melin and K Nathanson and S Domchek and A Jakubowska and J Lubinski and T Huzarski and A Osorio and A Lasa and Duran, {M (Mercedes)} and MI Tejada and J Godino and J Benitez and U Hamann and Mieke Kriege and N Hoogerbrugge and {van der Luijt}, RB and {van Asperen}, CJ and P Devilee and EJ Meijers-Heijboer and MJ Blok and CM Aalfs and F Hogervorst and M Rookus and M Cook and C Oliver and D Frost and D Conroy and DG Evans and F Lalloo and G Pichert and R Davidson and T Cole and J Cook and J Paterson and S Hodgson and PJ Morrison and ME Porteous and L Walker and MJ Kennedy and H Dorkins and S Peock and AK Godwin and D Stoppa-Lyonnet and {de Pauw}, A and S Mazoyer and V Bonadona and C Lasset and H Dreyfus and D Leroux and A Hardouin and P Berthet and L Faivre and C Loustalot and T Noguchi and H Sobol and E Rouleau and C Nogues and M Frenay and L Venat-Bouvet 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 AC Dressler and D Gschwantler-Kaulich and G Pfeiler and TVO Hansen and L Jnson and BA Agnarsson and T Kirchhoff and K Offit and V Devlin and A Dutra-Clarke and M Piedmonte and GC Rodriguez and K Wakeley and JF Boggess and J Basil and PE Schwartz and SV Blank and AE Toland and M Montagna and C Casella and E Imyanitov and L Tihomirova and I Blanco and Lazaro, {C (Conxi)} and SJ Ramus and L Sucheston and BY Karlan and J Gross and R Schmutzler and B Wappenschmidt and C Engel and A Meindl and M Lochmann and N Arnold and S Heidemann and R Varon-Mateeva and D Niederacher and C Sutter and H Deissler and D Gadzicki and S Preisler-Adams and K Kast and I Schonbuchner and T Caldes and {de la Hoya}, M and K Aittomaki and H Nevanlinna and J Simard and AB Spurdle and H Holland and XQ Chen and R Platte and G Chenevix-Trench and DF Easton",

year = "2010",

doi = "10.1158/0008-5472.CAN-10-1907",

language = "Undefined/Unknown",

volume = "70",

pages = "9742--9754",

journal = "Cancer Research",

issn = "0008-5472",

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

number = "23",

}

Antoniou, AC, Beesley, J, McGuffog, L, Sinilnikova, OM, Healey, S, Neuhausen, SL, Ding, YC, Rebbeck, TR, Weitzel, JN, Lynch, HT, Isaacs, C, Ganz, PA, Tomlinson, G, Olopade, OI, Couch, FJ, Wang, XS, Lindor, NM, Pankratz, VS, Radice, P, Manoukian, S, Peissel, B, Zaffaroni, D, Barile, M, Viel, A, Allavena, A, Dall'Olio, V, Peterlongo, P, Szabo, CI, Zikan, M, Claes, K, Poppe, B, Foretova, L, Mai, PL, Greene, MH, Rennert, G, Lejbkowicz, F, Glendon, G, Ozcelik, H, Andrulis, IL, Thomassen, M, Gerdes, AM, Sunde, L, Cruger, D, Jensen, UB, Caligo, M, Friedman, E, Kaufman, B, Laitman, Y, Milgrom, R, Dubrovsky, M, Cohen, S, Borg, A, Jernstrom, H, Lindblom, A, Rantala, J, Stenmark-Askmalm, M, Melin, B, Nathanson, K, Domchek, S, Jakubowska, A, Lubinski, J, Huzarski, T, Osorio, A, Lasa, A, Duran, M, Tejada, MI, Godino, J, Benitez, J, Hamann, U, Kriege, M, Hoogerbrugge, N, van der Luijt, RB, van Asperen, CJ, Devilee, P, Meijers-Heijboer, EJ, Blok, MJ, Aalfs, CM, Hogervorst, F, Rookus, M, Cook, M, Oliver, C, Frost, D, Conroy, D, Evans, DG, Lalloo, F, Pichert, G, Davidson, R, Cole, T, Cook, J, Paterson, J, Hodgson, S, Morrison, PJ, Porteous, ME, Walker, L, Kennedy, MJ, Dorkins, H, Peock, S, Godwin, AK, Stoppa-Lyonnet, D, de Pauw, A, Mazoyer, S, Bonadona, V, Lasset, C, Dreyfus, H, Leroux, D, Hardouin, A, Berthet, P, Faivre, L, Loustalot, C, Noguchi, T, Sobol, H, Rouleau, E, Nogues, C, Frenay, M, Venat-Bouvet, L, Hopper, JL, Daly, MB, Terry, MB, John, EM, Buys, SS, Yassin, Y, Miron, A, Goldgar, D, Singer, CF, Dressler, AC, Gschwantler-Kaulich, D, Pfeiler, G, Hansen, TVO, Jnson, L, Agnarsson, BA, Kirchhoff, T, Offit, K, Devlin, V, Dutra-Clarke, A, Piedmonte, M, Rodriguez, GC, Wakeley, K, Boggess, JF, Basil, J, Schwartz, PE, Blank, SV, Toland, AE, Montagna, M, Casella, C, Imyanitov, E, Tihomirova, L, Blanco, I, Lazaro, C, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Schmutzler, R, Wappenschmidt, B, Engel, C, Meindl, A, Lochmann, M, Arnold, N, Heidemann, S, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Preisler-Adams, S, Kast, K, Schonbuchner, I, Caldes, T, de la Hoya, M, Aittomaki, K, Nevanlinna, H, Simard, J, Spurdle, AB, Holland, H, Chen, XQ, Platte, R, Chenevix-Trench, G & Easton, DF 2010, 'Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction', Cancer Research, vol. 70, no. 23, pp. 9742-9754. https://doi.org/10.1158/0008-5472.CAN-10-1907

TY - JOUR

T1 - Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

AU - Antoniou, AC

AU - Beesley, J

AU - McGuffog, L

AU - Sinilnikova, OM

AU - Healey, S

AU - Neuhausen, SL

AU - Ding, YC

AU - Rebbeck, TR

AU - Weitzel, JN

AU - Lynch, HT

AU - Isaacs, C

AU - Ganz, PA

AU - Tomlinson, G

AU - Olopade, OI

AU - Couch, FJ

AU - Wang, XS

AU - Lindor, NM

AU - Pankratz, VS

AU - Radice, P

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Barile, M

AU - Viel, A

AU - Allavena, A

AU - Dall'Olio, V

AU - Peterlongo, P

AU - Szabo, CI

AU - Zikan, M

AU - Claes, K

AU - Poppe, B (Bruce)

AU - Foretova, L

AU - Mai, PL

AU - Greene, MH

AU - Rennert, G

AU - Lejbkowicz, F

AU - Glendon, G

AU - Ozcelik, H

AU - Andrulis, IL

AU - Thomassen, Marga

AU - Gerdes, AM

AU - Sunde, L

AU - Cruger, D

AU - Jensen, UB

AU - Caligo, M

AU - Friedman, E

AU - Kaufman, B

AU - Laitman, Y

AU - Milgrom, R

AU - Dubrovsky, M

AU - Cohen, S

AU - Borg, A

AU - Jernstrom, H

AU - Lindblom, A

AU - Rantala, J

AU - Stenmark-Askmalm, M

AU - Melin, B

AU - Nathanson, K

AU - Domchek, S

AU - Jakubowska, A

AU - Lubinski, J

AU - Huzarski, T

AU - Osorio, A

AU - Lasa, A

AU - Duran, M (Mercedes)

AU - Tejada, MI

AU - Godino, J

AU - Benitez, J

AU - Hamann, U

AU - Kriege, Mieke

AU - Hoogerbrugge, N

AU - van der Luijt, RB

AU - van Asperen, CJ

AU - Devilee, P

AU - Meijers-Heijboer, EJ

AU - Blok, MJ

AU - Aalfs, CM

AU - Hogervorst, F

AU - Rookus, M

AU - Cook, M

AU - Oliver, C

AU - Frost, D

AU - Conroy, D

AU - Evans, DG

AU - Lalloo, F

AU - Pichert, G

AU - Davidson, R

AU - Cole, T

AU - Cook, J

AU - Paterson, J

AU - Hodgson, S

AU - Morrison, PJ

AU - Porteous, ME

AU - Walker, L

AU - Kennedy, MJ

AU - Dorkins, H

AU - Peock, S

AU - Godwin, AK

AU - Stoppa-Lyonnet, D

AU - de Pauw, A

AU - Mazoyer, S

AU - Bonadona, V

AU - Lasset, C

AU - Dreyfus, H

AU - Leroux, D

AU - Hardouin, A

AU - Berthet, P

AU - Faivre, L

AU - Loustalot, C

AU - Noguchi, T

AU - Sobol, H

AU - Rouleau, E

AU - Nogues, C

AU - Frenay, M

AU - Venat-Bouvet, L

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 - Dressler, AC

AU - Gschwantler-Kaulich, D

AU - Pfeiler, G

AU - Hansen, TVO

AU - Jnson, L

AU - Agnarsson, BA

AU - Kirchhoff, T

AU - Offit, K

AU - Devlin, V

AU - Dutra-Clarke, A

AU - Piedmonte, M

AU - Rodriguez, GC

AU - Wakeley, K

AU - Boggess, JF

AU - Basil, J

AU - Schwartz, PE

AU - Blank, SV

AU - Toland, AE

AU - Montagna, M

AU - Casella, C

AU - Imyanitov, E

AU - Tihomirova, L

AU - Blanco, I

AU - Lazaro, C (Conxi)

AU - Ramus, SJ

AU - Sucheston, L

AU - Karlan, BY

AU - Gross, J

AU - Schmutzler, R

AU - Wappenschmidt, B

AU - Engel, C

AU - Meindl, A

AU - Lochmann, M

AU - Arnold, N

AU - Heidemann, S

AU - Varon-Mateeva, R

AU - Niederacher, D

AU - Sutter, C

AU - Deissler, H

AU - Gadzicki, D

AU - Preisler-Adams, S

AU - Kast, K

AU - Schonbuchner, I

AU - Caldes, T

AU - de la Hoya, M

AU - Aittomaki, K

AU - Nevanlinna, H

AU - Simard, J

AU - Spurdle, AB

AU - Holland, H

AU - Chen, XQ

AU - Platte, R

AU - Chenevix-Trench, G

AU - Easton, DF

PY - 2010

Y1 - 2010

N2 - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42%

AB - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42%

U2 - 10.1158/0008-5472.CAN-10-1907

DO - 10.1158/0008-5472.CAN-10-1907

M3 - Article

C2 - 21118973

SN - 0008-5472

VL - 70

SP - 9742

EP - 9754

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -