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

Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
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/EBP?, 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.
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O'Reilly, Martin
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Samarajiwa, Shamith
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Dunning, Mark
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Peock, Susan
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Eccles, Diana
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Mazoyer, Sylvie
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Beesley, Jonathan
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Healey, Sue
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Caldas, Carlos
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Chenevix-Trench, Georgia
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Ponder, Bruce A.J.
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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.G., 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 A., Barkardottir, Rosa B., Chen, Xiaoqing, Beesley, Jonathan, Healey, Sue, Caldas, Carlos, Chenevix-Trench, Georgia and Ponder, Bruce A.J. (2012) Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. Breast Cancer Research, 14 (2), R63. (doi:10.1186/bcr3169). (PMID:22513257)

Record type: Article

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/EBP?, 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.

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Published date: 18 April 2012
Organisations: Cancer Sciences

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Local EPrints ID: 352330
URI: https://eprints.soton.ac.uk/id/eprint/352330
PURE UUID: bfa4b88c-8266-451f-a166-429b4d6b9083

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Date deposited: 10 May 2013 11:56
Last modified: 18 Jul 2017 04:15

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Contributors

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

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