Open Access Open Badges Research article

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

Ana-Teresa Maia1230*, Antonis C Antoniou3, Martin O'Reilly1, Shamith Samarajiwa12, Mark Dunning1, Christiana Kartsonaki3, Suet-Feung Chin12, Christina N Curtis1229, Lesley McGuffog3, Susan M Domchek4, EMBRACE3, Douglas F Easton3, Susan Peock3, Debra Frost3, D Gareth Evans5, Ros Eeles6, Louise Izatt7, Julian Adlard8, Diana Eccles9, GEMO Study Collaborators 10, Olga M Sinilnikova1112, Sylvie Mazoyer11, Dominique Stoppa-Lyonnet131415, Marion Gauthier-Villars13, Laurence Faivre1617, Laurence Venat-Bouvet18, Capucine Delnatte19, Heli Nevanlinna20, Fergus J Couch21, Andrew K Godwin22, Maria Adelaide Caligo23, SWE-BRCA, Rosa B Barkardottir2425, kConFab Investigators26, Xiaoqing Chen27, Jonathan Beesley27, Sue Healey27, Carlos Caldas1228, Georgia Chenevix-Trench27 and Bruce AJ Ponder12

Author Affiliations

1 Cambridge Research Institute - CRUK, Li Ka Shing Centre, Cancer Research UK, Robinson Way, Cambridge, CB2 0RE, UK

2 Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Robinson Way, Cambridge, CB2 0RE, UK

3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK

4 Department of Medicine, Hematology-Oncology, Abramson Cancer Center, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA

5 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Brunswick Street, Manchester, M13 9PL, UK

6 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Rd, Belmont, Sutton Surrey SM2 5NG, UK

7 Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, 7th floor, Borough Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK

8 Yorkshire Regional Genetics Service, Ward 10, 3rd Floor, Chapel Allerton Hospital Chapeltown Road, Leeds, LS7 4SA, UK

9 Wessex Clinical Genetics Service, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK

10 GEMO Study Collaborators: Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer, France

11 INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, Lyon, 7 rue Guillaume Paradin, 69008 Lyon, France

12 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France

13 Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm 75248 Paris cedex 05, France

14 Unité INSERM U830, Institut Curie, 26 rue d'Ulm 75248 Paris cedex 05, France

15 Université Paris Descartes, Faculté de Médecine, 12, rue de l'Ecole de Médecine 75270 Paris Cedex 06, France

16 Centre de Génétique, CHU Dijon, Université de Bourgogne, Dijon F-21000, France

17 Centre Georges François Leclerc, 1 Rue Professeur Marion 21000 Dijon, France

18 Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, Limoges, France

19 Centre René Gauducheau, Boulevard Jacques Monod 44805 St Herblain Cedex, Nantes, France

20 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. BOX 700, 00029 HUS, Finland

21 Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street Southwest Rochester, MN 55905, USA

22 University of Kansas Medical Center, 3901 Rainbow Boulevard, KS City, KS 66160, USA

23 Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Lungarno Antonio Pacinotti, 43 56126 Pisa, Italy

24 Department of Pathology, Landspitali University Hospital, Reykjavik 101, Iceland

25 Faculty of Medicine, University of Iceland, Vatnsmýrarvegur 16, level 4 Reykjavik, Iceland

26 Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne, VIC 8006, Australia

27 Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia

28 Cambridge Experimental Cancer Medicine Centre, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

29 Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine, Department of Biomedical Sciences and Medicine, University of Algarve, Portugal

30 Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine, Department of Biomedical Sciences and Medicine, Gambelas Campus, Building 7, University of Algarve, 8005-139 Faro, Portugal

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Breast Cancer Research 2012, 14:R63  doi:10.1186/bcr3169

Published: 18 April 2012



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.


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.


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).


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.