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 W. Karlsson; Marie Stenmark Askmalm; Gisela Barbany Bustinza; Katherine L Nathanson; Susan M Domchek; Timothy R Rebbeck; Javier Benítez; 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; Ontario Cancer Genetics Network

doi:http://dx.doi.org/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 W. Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L Nathanson, Susan M Domchek, Timothy R Rebbeck, Javier Benítez, 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, Ontario Cancer Genetics Network

21 Citationer (Scopus)

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 5 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.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	20
Udgave nummer	23
Sider (fra-til)	4732-47
Antal sider	16
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddr388
Status	Udgivet - 1 dec. 2011

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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., ... Ontario Cancer Genetics Network (2011). Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Human Molecular Genetics, 20(23), 4732-47. https://doi.org/10.1093/hmg/ddr388

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, PW, Askmalm, MS, Bustinza, GB, Nathanson, KL, Domchek, SM, Rebbeck, TR, Benítez, 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 & Ontario Cancer Genetics Network 2011, 'Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers', Human Molecular Genetics, bind 20, nr. 23, s. 4732-47. https://doi.org/10.1093/hmg/ddr388

@article{e1fa1144c2c3426eaecb15d1f2d84939,

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 5 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 Karlsson, {Per W.} and Askmalm, {Marie Stenmark} and Bustinza, {Gisela Barbany} and Nathanson, {Katherine L} and Domchek, {Susan M} and Rebbeck, {Timothy R} and Javier Ben{\'i}tez 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 Gerdes, {Anne-Marie Ax{\o}}",

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doi = "http://dx.doi.org/10.1093/hmg/ddr388",

language = "English",

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pages = "4732--47",

journal = "Human Molecular Genetics",

issn = "0964-6906",

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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 W.

AU - Askmalm, Marie Stenmark

AU - Bustinza, Gisela Barbany

AU - Nathanson, Katherine L

AU - Domchek, Susan M

AU - Rebbeck, Timothy R

AU - Benítez, 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 - Ontario Cancer Genetics Network

PY - 2011/12/1

Y1 - 2011/12/1

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 5 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 5 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 - http://dx.doi.org/10.1093/hmg/ddr388

DO - http://dx.doi.org/10.1093/hmg/ddr388

M3 - Journal 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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