Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers

Ana-Teresa Maia, Antonis C Antoniou, Martin O'Reilly, Shamith Samarajiwa, Mark Dunning, Christiana Kartsonaki, Suet-Feung Chin, Christina N Curtis, Lesley McGuffog, Susan M Domchek, Douglas F Easton, Susan Peock, Debra Frost, D Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Diana Eccles, Olga M Sinilnikova, Sylvie Mazoyer & 18 others Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Laurence Faivre, Laurence Venat-Bouvet, Capucine Delnatte, Heli Nevanlinna, Fergus J Couch, Andrew K Godwin, Maria Adelaide Caligo, Rosa B Barkardottir, Xiaoqing Chen, Jonathan Beesley, Sue Healey, Carlos Caldas, Georgia Chenevix-Trench, Bruce A J Ponder, EMBRACE, Zosia Miedzybrodzka

Research output: Contribution to journalArticle

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Abstract

Introduction
Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.

Methods
We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.

Results
We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).

Conclusions
Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
Original languageEnglish
Article numberR63
JournalBreast Cancer Research
Volume14
Issue number2
DOIs
Publication statusPublished - 18 Apr 2012

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Haplotypes
Breast Neoplasms
Mutation
Single Nucleotide Polymorphism
Penetrance
Breast
Alleles
Transcription Factors
Gene Expression
Germ-Line Mutation
Computer Simulation
Carrier Proteins
Confidence Intervals
Technology
Cell Line

Cite this

Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. / Maia, Ana-Teresa; Antoniou, Antonis C; O'Reilly, Martin; Samarajiwa, Shamith; Dunning, Mark; Kartsonaki, Christiana; Chin, Suet-Feung; Curtis, Christina N; McGuffog, Lesley; Domchek, Susan M; Easton, Douglas F; Peock, Susan; Frost, Debra; Evans, D Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Eccles, Diana; Sinilnikova, Olga M; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Faivre, Laurence; Venat-Bouvet, Laurence; Delnatte, Capucine; Nevanlinna, Heli; Couch, Fergus J; Godwin, Andrew K; Caligo, Maria Adelaide; Barkardottir, Rosa B; Chen, Xiaoqing; Beesley, Jonathan; Healey, Sue; Caldas, Carlos; Chenevix-Trench, Georgia; Ponder, Bruce A J; EMBRACE ; Miedzybrodzka, Zosia.

In: Breast Cancer Research, Vol. 14, No. 2, R63, 18.04.2012.

Research output: Contribution to journalArticle

Maia, A-T, Antoniou, AC, O'Reilly, M, Samarajiwa, S, Dunning, M, Kartsonaki, C, Chin, S-F, Curtis, CN, McGuffog, L, Domchek, SM, Easton, DF, Peock, S, Frost, D, Evans, DG, Eeles, R, Izatt, L, Adlard, J, Eccles, D, Sinilnikova, OM, Mazoyer, S, Stoppa-Lyonnet, D, Gauthier-Villars, M, Faivre, L, Venat-Bouvet, L, Delnatte, C, Nevanlinna, H, Couch, FJ, Godwin, AK, Caligo, MA, Barkardottir, RB, Chen, X, Beesley, J, Healey, S, Caldas, C, Chenevix-Trench, G, Ponder, BAJ, EMBRACE & Miedzybrodzka, Z 2012, 'Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers', Breast Cancer Research, vol. 14, no. 2, R63. https://doi.org/10.1186/bcr3169
Maia A-T, Antoniou AC, O'Reilly M, Samarajiwa S, Dunning M, Kartsonaki C et al. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. Breast Cancer Research. 2012 Apr 18;14(2). R63. https://doi.org/10.1186/bcr3169
Maia, Ana-Teresa ; Antoniou, Antonis C ; O'Reilly, Martin ; Samarajiwa, Shamith ; Dunning, Mark ; Kartsonaki, Christiana ; Chin, Suet-Feung ; Curtis, Christina N ; McGuffog, Lesley ; Domchek, Susan M ; Easton, Douglas F ; Peock, Susan ; Frost, Debra ; Evans, D Gareth ; Eeles, Ros ; Izatt, Louise ; Adlard, Julian ; Eccles, Diana ; Sinilnikova, Olga M ; Mazoyer, Sylvie ; Stoppa-Lyonnet, Dominique ; Gauthier-Villars, Marion ; Faivre, Laurence ; Venat-Bouvet, Laurence ; Delnatte, Capucine ; Nevanlinna, Heli ; Couch, Fergus J ; Godwin, Andrew K ; Caligo, Maria Adelaide ; Barkardottir, Rosa B ; Chen, Xiaoqing ; Beesley, Jonathan ; Healey, Sue ; Caldas, Carlos ; Chenevix-Trench, Georgia ; Ponder, Bruce A J ; EMBRACE ; Miedzybrodzka, Zosia. / Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. In: Breast Cancer Research. 2012 ; Vol. 14, No. 2.
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abstract = "IntroductionCis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.MethodsWe combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.ResultsWe identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95{\%} confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).ConclusionsOur work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.",
author = "Ana-Teresa Maia and Antoniou, {Antonis C} and Martin O'Reilly and Shamith Samarajiwa and Mark Dunning and Christiana Kartsonaki and Suet-Feung Chin and Curtis, {Christina N} and Lesley McGuffog and Domchek, {Susan M} and Easton, {Douglas F} and Susan Peock and Debra Frost and Evans, {D Gareth} and Ros Eeles and Louise Izatt and Julian Adlard and Diana Eccles and Sinilnikova, {Olga M} and Sylvie Mazoyer and Dominique Stoppa-Lyonnet and Marion Gauthier-Villars and Laurence Faivre and Laurence Venat-Bouvet and Capucine Delnatte and Heli Nevanlinna and Couch, {Fergus J} and Godwin, {Andrew K} and Caligo, {Maria Adelaide} and Barkardottir, {Rosa B} and Xiaoqing Chen and Jonathan Beesley and Sue Healey and Carlos Caldas and Georgia Chenevix-Trench and Ponder, {Bruce A J} and EMBRACE and Zosia Miedzybrodzka",
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T1 - Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers

AU - Maia, Ana-Teresa

AU - Antoniou, Antonis C

AU - O'Reilly, Martin

AU - Samarajiwa, Shamith

AU - Dunning, Mark

AU - Kartsonaki, Christiana

AU - Chin, Suet-Feung

AU - Curtis, Christina N

AU - McGuffog, Lesley

AU - Domchek, Susan M

AU - Easton, Douglas F

AU - Peock, Susan

AU - Frost, Debra

AU - Evans, D Gareth

AU - Eeles, Ros

AU - Izatt, Louise

AU - Adlard, Julian

AU - Eccles, Diana

AU - Sinilnikova, Olga M

AU - Mazoyer, Sylvie

AU - Stoppa-Lyonnet, Dominique

AU - Gauthier-Villars, Marion

AU - Faivre, Laurence

AU - Venat-Bouvet, Laurence

AU - Delnatte, Capucine

AU - Nevanlinna, Heli

AU - Couch, Fergus J

AU - Godwin, Andrew K

AU - Caligo, Maria Adelaide

AU - Barkardottir, Rosa B

AU - Chen, Xiaoqing

AU - Beesley, Jonathan

AU - Healey, Sue

AU - Caldas, Carlos

AU - Chenevix-Trench, Georgia

AU - Ponder, Bruce A J

AU - EMBRACE

AU - Miedzybrodzka, Zosia

PY - 2012/4/18

Y1 - 2012/4/18

N2 - IntroductionCis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.MethodsWe combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.ResultsWe identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).ConclusionsOur work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.

AB - IntroductionCis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.MethodsWe combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.ResultsWe identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).ConclusionsOur work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.

U2 - 10.1186/bcr3169

DO - 10.1186/bcr3169

M3 - Article

VL - 14

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 2

M1 - R63

ER -