TY - JOUR
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. G.
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 A.
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.
PY - 2012/4/18
Y1 - 2012/4/18
N2 - 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/EBPα, 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.
AB - 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/EBPα, 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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U2 - 10.1186/bcr3169
DO - 10.1186/bcr3169
M3 - Article
C2 - 22513257
AN - SCOPUS:84859786757
SN - 1465-5411
VL - 14
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 2
M1 - R63
ER -