1. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
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Carlos Caldas, D G R Evans, Ana-Teresa Maia, Antonis C. Antoniou, Sue Healey, Jonathan Beesley, Ros Eeles, Andrew K. Godwin, Bruce A.J. Ponder, Debra Frost, Marion Gauthier-Villars, Capucine Delnatte, Olga M. Sinilnikova, Sylvie Mazoyer, Diana Eccles, Christina Curtis, Lesley McGuffog, Shamith A. Samarajiwa, Louise Izatt, Rosa B. Barkardottir, Julian Adlard, Martin O'Reilly, Suet-Feung Chin, Xiaoqing Chen, Laurence Venat-Bouvet, Georgia Chenevix-Trench, Christiana Kartsonaki, Laurence Faivre, Douglas F. Easton, Mark J Dunning, Maria A. Caligo, Susan M. Domchek, Dominique Stoppa-Lyonnet, Susan Peock, Fergus J. Couch, Heli Nevanlinna, Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), University of Cambridge [UK] (CAM), Department of Oncology, University of Cambridge [UK] (CAM)-Addenbrooke's Hospital, Institute for Biotechnology and Bioengineering (IBB), Technical University of Lisbon, Centre for Cancer Genetic Epidemiology, Abramson Cancer Center, University of Pennsylvania [Philadelphia], Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Wessex Clinical Genetics Service, Princess Anne Hospital, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Centre René Gauducheau, CRLCC René Gauducheau, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Section of Genetic Oncology, Pisa University Hospital-University of Pisa - Università di Pisa, Department of Pathology, Landspitali University Hospital, Faculty of Medicine, University of Iceland [Reykjavik], Queensland Institute of Medical Research, Cambridge Experimental Cancer Medicine Centre, Li Ka Shing Centre, This work was supported by a Breast Cancer Research Foundation grant to ATM and BAJP, the University of Cambridge, Cancer Research UK, Hutchison Whampoa Limited and NIHR Cambridge Biomedical Research Centre. BAJP is the Li Ka Shing Professor of Oncology at the University of Cambridge. ACA is a Cancer Research - UK Senior Cancer Research Fellow. The CIMBA data management and analysis is supported by Cancer Research - UK., GEMO Study Collaborators, SWE-BRCA, kConFab Investigators, Cambridge Research Institute (CRUK), Cancer Research UK - Li Ka Shing Centre, University of Cambridge [UK] (CAM) - Addenbrooke's Hospital, Manchester Academic Health Sciences Centre - Central Manchester University Hospitals, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon - Université de Lyon - Centre Léon Bérard [Lyon] - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon] - Hospices Civils de Lyon (HCL), INSTITUT CURIE, Université Paris Descartes - Paris 5 (UPD5) - Institut Curie - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), University of Kansas Medical Center, Pisa University Hospital - University of Pisa [Pisa], University of Pennsylvania, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], and BMC, Ed.
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Heterozygote ,Colorectal-cancer ,Predisposition ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Single-nucleotide polymorphism ,Regulatory Sequences, Nucleic Acid ,Biology ,Polymorphism, Single Nucleotide ,Association ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Germline mutation ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Reference Values ,medicine ,Humans ,Genetic Predisposition to Disease ,Allelic imbalance ,Gene-expression ,Allele ,Promoter Regions, Genetic ,skin and connective tissue diseases ,030304 developmental biology ,Medicine(all) ,BRCA2 Protein ,Genetics ,0303 health sciences ,Human genome ,Carcinoma ,Haplotype ,medicine.disease ,Penetrance ,Common ,3. Good health ,Gene Expression Regulation, Neoplastic ,Minor allele frequency ,Gene Expression Regulation ,Haplotypes ,Regulatory sequence ,030220 oncology & carcinogenesis ,Beadarray ,Cancer research ,Female ,Cell-line ,Transcription Factors ,Research 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 alpha, 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. Core Genomics team at Cambridge Research Institute; Breast Cancer Research Foundation; University of Cambridge; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385]; Hutchison Whampoa Limited; NIHR Cambridge Biomedical Research Centre; Cancer Genetics Network; Marjorie Cohen Foundation; NIHR; Royal Marsden NHS Foundation Trust; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-en!"; Helsinki University Central Hospital; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; NIH [CA128978]; Breast Cancer Specialized Program of Research Excellence (SPORE) [CA116167]; Komen Foundation for the Cure; Eileen Stein Jacoby Fund; University of Kansas Cancer Center; Kansas Bioscience Authority; Tumour Tuscany Institute [AOOGRT/0011780/Q.30.11]; NHMRC; National Breast Cancer Foundation; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council South Australia; Cancer Foundation of Western Australia; [U01CA69631]; [5U01CA113916]; Cancer Research UK [19275, 11022, 10118, 19556, 11174]; National Institute for Health Research [NF-SI-0611-10154, NF-SI-0510-10096]
- Published
- 2012
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