Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

David G. Cox; Jacques Simard; Daniel Sinnett; Yosr Hamdi; Penny Soucy; Manon Ouimet; Laure Barjhoux; Carole Verny-Pierre; Lesley McGuffog; Sue Healey; Csilla Szabo; Mark H. Greene; Phuong L. Mai; Irene L. Andrulis; Mads Thomassen; Anne-Marie Gerdes; Maria A. Caligo; Eitan Friedman; Yael Laitman; Bella Kaufman; Shani S. Paluch; Åke Borg; Per Karlsson; Marie Stenmark Askmalm; Gisela Barbany Bustinza; Katherine L. Nathanson; Susan M. Domchek; Timothy R. Rebbeck; Javier Benitez; Ute Hamann; Matti A. Rookus; Ans M. W. van den Ouweland; Margreet G. E. M. Ausems; Cora M. Aalfs; Christi J. van Asperen; Peter Devilee; Hans J. J. P. Gille; Susan Peock; Debra Frost; D. Gareth Evans; Ros Eeles; Louise Izatt; Julian Adlard; Joan Paterson; Jacqueline Eason; Andrew K. Godwin; Marie-Alice Remon; Virginie Moncoutier; Marion Gauthier-Villars; Christine Lasset; Sophie Giraud; Agnes Hardouin; Pascaline Berthet; Hagay Sobol; Francois Eisinger; Brigitte Bressac de Paillerets; Olivier Caron; Capucine Delnatte; David Goldgar; Alex Miron; Hilmi Ozcelik; Saundra Buys; Melissa C. Southey; Mary Beth Terry; Christian F. Singer; Anne-Catharina Dressler; Muy-Kheng Tea; Thomas V. O. Hansen; Oskar Johannsson; Marion Piedmonte; Gustavo C. Rodriguez; Jack B. Basil; Stephanie Blank; Amanda E. Toland; Marco Montagna; Claudine Isaacs; Ignacio Blanco; Simon A. Gayther; Kirsten B. Moysich; Rita K. Schmutzler; Barbara Wappenschmidt; Christoph Engel; Alfons Meindl; Nina Ditsch; Norbert Arnold; Dieter Niederacher; Christian Sutter; Dorothea Gadzicki; Britta Fiebig; Trinidad Caldes; Rachel Laframboise; Heli Nevanlinna; Xiaoqing Chen; Jonathan Beesley; Amanda B. Spurdle; Susan L. Neuhausen; Yuan C. Ding; Fergus J. Couch; Xianshu Wang; Paolo Peterlongo; Siranoush Manoukian; Loris Bernard; Paolo Radice; Douglas F. Easton; Georgia Chenevix-Trench; Antonis C. Antoniou; Dominique Stoppa-Lyonnet; Sylvie Mazoyer; Olga M. Sinilnikova; Håkan Olsson

doi:10.1093/hmg/ddr388

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella KaufmanShani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benitez, Ute Hamann, Matti A. Rookus, Ans M. W. van den Ouweland, Margreet G. E. M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J. J. P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnes Hardouin, Pascaline Berthet, Hagay Sobol, Francois Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas V. O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M. Sinilnikova, Håkan Olsson

Breastcancer-genetics

Skåne University Hospital

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

Abstract

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Original language	English
Pages (from-to)	4732-4747
Journal	Human Molecular Genetics
Volume	20
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddr388
Publication status	Published - 2011

Subject classification (UKÄ)

Medical Genetics

UN SDGs

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

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10.1093/hmg/ddr388

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Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A.-M., Caligo, M. A., Friedman, E., Laitman, Y., ... Olsson, H. (2011). Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Human Molecular Genetics, 20(23), 4732-4747. https://doi.org/10.1093/hmg/ddr388

@article{506e84e6e4664b78b7828f94311bf29a,

title = "Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers",

abstract = "Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.",

author = "Cox, {David G.} and Jacques Simard and Daniel Sinnett and Yosr Hamdi and Penny Soucy and Manon Ouimet and Laure Barjhoux and Carole Verny-Pierre and Lesley McGuffog and Sue Healey and Csilla Szabo and Greene, {Mark H.} and Mai, {Phuong L.} and Andrulis, {Irene L.} and Mads Thomassen and Anne-Marie Gerdes and Caligo, {Maria A.} and Eitan Friedman and Yael Laitman and Bella Kaufman and Paluch, {Shani S.} and {\AA}ke Borg and Per Karlsson and Askmalm, {Marie Stenmark} and Bustinza, {Gisela Barbany} and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Rebbeck, {Timothy R.} and Javier Benitez and Ute Hamann and Rookus, {Matti A.} and {van den Ouweland}, {Ans M. W.} and Ausems, {Margreet G. E. M.} and Aalfs, {Cora M.} and {van Asperen}, {Christi J.} and Peter Devilee and Gille, {Hans J. J. P.} and Susan Peock and Debra Frost and Evans, {D. Gareth} and Ros Eeles and Louise Izatt and Julian Adlard and Joan Paterson and Jacqueline Eason and Godwin, {Andrew K.} and Marie-Alice Remon and Virginie Moncoutier and Marion Gauthier-Villars and Christine Lasset and Sophie Giraud and Agnes Hardouin and Pascaline Berthet and Hagay Sobol and Francois Eisinger and {de Paillerets}, {Brigitte Bressac} and Olivier Caron and Capucine Delnatte and David Goldgar and Alex Miron and Hilmi Ozcelik and Saundra Buys and Southey, {Melissa C.} and Terry, {Mary Beth} and Singer, {Christian F.} and Anne-Catharina Dressler and Muy-Kheng Tea and Hansen, {Thomas V. O.} and Oskar Johannsson and Marion Piedmonte and Rodriguez, {Gustavo C.} and Basil, {Jack B.} and Stephanie Blank and Toland, {Amanda E.} and Marco Montagna and Claudine Isaacs and Ignacio Blanco and Gayther, {Simon A.} and Moysich, {Kirsten B.} and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Christoph Engel and Alfons Meindl and Nina Ditsch and Norbert Arnold and Dieter Niederacher and Christian Sutter and Dorothea Gadzicki and Britta Fiebig and Trinidad Caldes and Rachel Laframboise and Heli Nevanlinna and Xiaoqing Chen and Jonathan Beesley and Spurdle, {Amanda B.} and Neuhausen, {Susan L.} and Ding, {Yuan C.} and Couch, {Fergus J.} and Xianshu Wang and Paolo Peterlongo and Siranoush Manoukian and Loris Bernard and Paolo Radice and Easton, {Douglas F.} and Georgia Chenevix-Trench and Antoniou, {Antonis C.} and Dominique Stoppa-Lyonnet and Sylvie Mazoyer and Sinilnikova, {Olga M.} and H{\aa}kan Olsson",

year = "2011",

doi = "10.1093/hmg/ddr388",

language = "English",

volume = "20",

pages = "4732--4747",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "23",

}

Cox, DG, Simard, J, Sinnett, D, Hamdi, Y, Soucy, P, Ouimet, M, Barjhoux, L, Verny-Pierre, C, McGuffog, L, Healey, S, Szabo, C, Greene, MH, Mai, PL, Andrulis, IL, Thomassen, M, Gerdes, A-M, Caligo, MA, Friedman, E, Laitman, Y, Kaufman, B, Paluch, SS, Borg, Å, Karlsson, P, Askmalm, MS, Bustinza, GB, Nathanson, KL, Domchek, SM, Rebbeck, TR, Benitez, J, Hamann, U, Rookus, MA, van den Ouweland, AMW, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Devilee, P, Gille, HJJP, Peock, S, Frost, D, Evans, DG, Eeles, R, Izatt, L, Adlard, J, Paterson, J, Eason, J, Godwin, AK, Remon, M-A, Moncoutier, V, Gauthier-Villars, M, Lasset, C, Giraud, S, Hardouin, A, Berthet, P, Sobol, H, Eisinger, F, de Paillerets, BB, Caron, O, Delnatte, C, Goldgar, D, Miron, A, Ozcelik, H, Buys, S, Southey, MC, Terry, MB, Singer, CF, Dressler, A-C, Tea, M-K, Hansen, TVO, Johannsson, O, Piedmonte, M, Rodriguez, GC, Basil, JB, Blank, S, Toland, AE, Montagna, M, Isaacs, C, Blanco, I, Gayther, SA, Moysich, KB, Schmutzler, RK, Wappenschmidt, B, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Niederacher, D, Sutter, C, Gadzicki, D, Fiebig, B, Caldes, T, Laframboise, R, Nevanlinna, H, Chen, X, Beesley, J, Spurdle, AB, Neuhausen, SL, Ding, YC, Couch, FJ, Wang, X, Peterlongo, P, Manoukian, S, Bernard, L, Radice, P, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Stoppa-Lyonnet, D, Mazoyer, S, Sinilnikova, OM & Olsson, H 2011, 'Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers', Human Molecular Genetics, vol. 20, no. 23, pp. 4732-4747. https://doi.org/10.1093/hmg/ddr388

TY - JOUR

T1 - Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

AU - Cox, David G.

AU - Simard, Jacques

AU - Sinnett, Daniel

AU - Hamdi, Yosr

AU - Soucy, Penny

AU - Ouimet, Manon

AU - Barjhoux, Laure

AU - Verny-Pierre, Carole

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Szabo, Csilla

AU - Greene, Mark H.

AU - Mai, Phuong L.

AU - Andrulis, Irene L.

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Caligo, Maria A.

AU - Friedman, Eitan

AU - Laitman, Yael

AU - Kaufman, Bella

AU - Paluch, Shani S.

AU - Borg, Åke

AU - Karlsson, Per

AU - Askmalm, Marie Stenmark

AU - Bustinza, Gisela Barbany

AU - Nathanson, Katherine L.

AU - Domchek, Susan M.

AU - Rebbeck, Timothy R.

AU - Benitez, Javier

AU - Hamann, Ute

AU - Rookus, Matti A.

AU - van den Ouweland, Ans M. W.

AU - Ausems, Margreet G. E. M.

AU - Aalfs, Cora M.

AU - van Asperen, Christi J.

AU - Devilee, Peter

AU - Gille, Hans J. J. P.

AU - Peock, Susan

AU - Frost, Debra

AU - Evans, D. Gareth

AU - Eeles, Ros

AU - Izatt, Louise

AU - Adlard, Julian

AU - Paterson, Joan

AU - Eason, Jacqueline

AU - Godwin, Andrew K.

AU - Remon, Marie-Alice

AU - Moncoutier, Virginie

AU - Gauthier-Villars, Marion

AU - Lasset, Christine

AU - Giraud, Sophie

AU - Hardouin, Agnes

AU - Berthet, Pascaline

AU - Sobol, Hagay

AU - Eisinger, Francois

AU - de Paillerets, Brigitte Bressac

AU - Caron, Olivier

AU - Delnatte, Capucine

AU - Goldgar, David

AU - Miron, Alex

AU - Ozcelik, Hilmi

AU - Buys, Saundra

AU - Southey, Melissa C.

AU - Terry, Mary Beth

AU - Singer, Christian F.

AU - Dressler, Anne-Catharina

AU - Tea, Muy-Kheng

AU - Hansen, Thomas V. O.

AU - Johannsson, Oskar

AU - Piedmonte, Marion

AU - Rodriguez, Gustavo C.

AU - Basil, Jack B.

AU - Blank, Stephanie

AU - Toland, Amanda E.

AU - Montagna, Marco

AU - Isaacs, Claudine

AU - Blanco, Ignacio

AU - Gayther, Simon A.

AU - Moysich, Kirsten B.

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Ditsch, Nina

AU - Arnold, Norbert

AU - Niederacher, Dieter

AU - Sutter, Christian

AU - Gadzicki, Dorothea

AU - Fiebig, Britta

AU - Caldes, Trinidad

AU - Laframboise, Rachel

AU - Nevanlinna, Heli

AU - Chen, Xiaoqing

AU - Beesley, Jonathan

AU - Spurdle, Amanda B.

AU - Neuhausen, Susan L.

AU - Ding, Yuan C.

AU - Couch, Fergus J.

AU - Wang, Xianshu

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Bernard, Loris

AU - Radice, Paolo

AU - Easton, Douglas F.

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C.

AU - Stoppa-Lyonnet, Dominique

AU - Mazoyer, Sylvie

AU - Sinilnikova, Olga M.

AU - Olsson, Håkan

PY - 2011

Y1 - 2011

N2 - Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

AB - Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

U2 - 10.1093/hmg/ddr388

DO - 10.1093/hmg/ddr388

M3 - Article

SN - 0964-6906

VL - 20

SP - 4732

EP - 4747

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 23

ER -

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

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