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 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; Ontario Cancer Genetics Network; Zofia Miedzybrodzka

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 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, Ontario Cancer Genetics Network, Zofia Miedzybrodzka

Applied Medicine

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

25 Citations (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 = 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
Number of pages	16
Journal	Human Molecular Genetics
Volume	20
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddr388
Publication status	Published - 1 Dec 2011

Keywords

alleles
BRCA1 protein
breast neoplasms
electrophoretic mobility shift assay
female
genes, reporter
genetic association studies
genetic predisposition to disease
haplotypes
HeLa cells
heterozygote
humans
linkage disequilibrium
luciferases
mutation
polymorphism, single nucleotide
risk factors

UN SDGs

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

Access to Document

10.1093/hmg/ddr388

Cite this

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., ... Miedzybrodzka, Z. (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

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, 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, Ontario Cancer Genetics Network & Miedzybrodzka, Z 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

@article{bf5b027c97d2438f9c09695ff7ee9f36,

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.",

keywords = "alleles, BRCA1 protein, breast neoplasms, electrophoretic mobility shift assay, female, genes, reporter, genetic association studies, genetic predisposition to disease, haplotypes, HeLa cells, heterozygote, humans, linkage disequilibrium, luciferases, mutation, polymorphism, single nucleotide, risk factors",

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 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 {Ontario Cancer Genetics Network} and Zofia Miedzybrodzka",

year = "2011",

month = dec,

day = "1",

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",

}

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 - 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 - Ontario Cancer Genetics Network

AU - Miedzybrodzka, Zofia

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 = 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.

KW - alleles

KW - BRCA1 protein

KW - breast neoplasms

KW - electrophoretic mobility shift assay

KW - female

KW - genes, reporter

KW - genetic association studies

KW - genetic predisposition to disease

KW - haplotypes

KW - HeLa cells

KW - heterozygote

KW - humans

KW - linkage disequilibrium

KW - luciferases

KW - mutation

KW - polymorphism, single nucleotide

KW - risk factors

U2 - 10.1093/hmg/ddr388

DO - 10.1093/hmg/ddr388

M3 - Article

C2 - 21890493

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this