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

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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/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.

Details

Authors
  • 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
  • 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
Research areas and keywords

Keywords

  • BRCA2 Protein, Female, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Haplotypes, Heterozygote, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Reference Values, Regulatory Sequences, Nucleic Acid, Transcription Factors
Original languageEnglish
Article numberR63
JournalBreast Cancer Research
Volume14
Issue number2
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes