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

Ana-Teresa Maia 1, 2, 3, * Antonis Antoniou 4 Martin O'Reilly 1 Shamith Samarajiwa 2, 1 Mark Dunning 1 Christiana Kartsonaki 4 Suet-Feung Chin 1, 2 Christina Curtis 1, 2, 3 Lesley Mcguffog 4 Susan Domchek 5 Douglas Easton 4 Susan Peock 4 Debra Frost 4 D Evans 6 Ros Eeles 7 Louise Izatt 8 Julian Adlard 9 Diana Eccles 10 Olga Sinilnikova 11, 12 Sylvie Mazoyer 11 Dominique Stoppa-Lyonnet 13, 14 Marion Gauthier-Villars 13 Laurence Faivre 15, 16 Laurence Venat-Bouvet 17 Capucine Delnatte 18 Heli Nevanlinna 19 Fergus Couch 20 Andrew Godwin 21 Maria Caligo 22 Rosa Barkardottir 23, 24 Xiaoqing Chen 25 Jonathan Beesley 25 Sue Healey 25 Carlos Caldas 1, 2, 26 Georgia Chenevix-Trench 25 Bruce Ponder 1, 2
Abstract : 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/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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Article dans une revue
Breast Cancer Research, BioMed Central, 2012, 14 (2), pp.R63. 〈10.1186/bcr3169〉
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Soumis le : jeudi 17 mai 2012 - 13:04:58
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Ana-Teresa Maia, Antonis Antoniou, Martin O'Reilly, Shamith Samarajiwa, Mark Dunning, et al.. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers.. Breast Cancer Research, BioMed Central, 2012, 14 (2), pp.R63. 〈10.1186/bcr3169〉. 〈inserm-00698626〉

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