Abstract
Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3′- untranslated regions (3′-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3′-UTR and one in BRCA2 3′-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3′-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3′-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.
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Acknowledgements
Financial support for GENESIS was provided by the Ligue Nationale contre le Cancer (three grants: PRE05/DSL, PRE07/DSL, PRE11/NA), the French National Institute of Cancer (Grant INCa n°2008-029/LL-LC) and the comprehensive cancer center SiRIC (Site de Recherche Intégrée sur le Cancer: Grant INCa-DGOS-4654). We thank the genetic epidemiology platform (the PIGE, Plateforme d'Investigation en Génétique et Epidémiologie: SEM, M Marcou, D Le Gal, L Toulemonde, J Beauvallet, N Mebirouk, E Cavaciuti, A Fescia, the biological resource center (CV-P, LB, VS) and all the GENESIS collaborating cancer clinics (Clinique Sainte Catherine, Avignon: H Dreyfus; Hôpital Saint Jacques, Besançon: M-A Collonge-Rame; Institut Bergonié, Bordeaux: M Longy, A Floquet, E Barouk-Simonet; CHU, Brest: S Audebert; Centre François Baclesse, Caen: P Berthet; Hôpital Dieu, Chambéry: S Fert-Ferrer; Centre Jean Perrin, Clermont-Ferrand: Y-J Bignon; Hôpital Pasteur, Colmar: J-M Limacher; Hôpital d’Enfants CHU – Centre Georges François Leclerc, Dijon: L Faivre-Olivier; CHU, Fort de France: O Bera; CHU Albert Michallon, Grenoble: D Leroux; Hôpital Flaubert, Le Havre: V Layet; Centre Oscar Lambret, Lille: P Vennin†, C Adenis; Hôpital Jeanne de Flandre, Lille: S Lejeune-Dumoulin, S Manouvier-Hanu; CHRU Dupuytren, Limoges: L Venat-Bouvet; Centre Léon Bérard, Lyon: C Lasset, V Bonadona; Hôpital Edouard Herriot, Lyon: S Giraud; Institut Paoli-Calmettes, Marseille: F Eisinger, L Huiart; Centre Val d’Aurelle – Paul Lamarque, Montpellier: I Coupier; CHU Arnaud de Villeneuve, Montpellier: I Coupier, P Pujol; Centre René Gauducheau, Nantes: C Delnatte; Centre Catherine de Sienne, Nantes: A Lortholary; Centre Antoine Lacassagne, Nice: M Frénay, V Mari; Hôpital Caremeau, Nîmes: J Chiesa; Réseau Oncogénétique Poitou Charente, Niort: P Gesta; Institut Curie, Paris: D Stoppa-Lyonnet, M Gauthier-Villars, B Buecher, A de Pauw, C Abadie, M Belotti; Hôpital Saint-Louis, Paris: O Cohen-Haguenauer; Centre Viggo-Petersen, Paris: F Cornélis; Hôpital Tenon, Paris: A Fajac; GH Pitié Salpétrière et Hôpital Beaujon, Paris: C Colas, F Soubrier, P Hammel, A Fajac; Institut Jean Godinot, Reims: C Pennet, TD Nguyen; Polyclinique Courlancy, Reims: L Demange†, C Pennet; Centre Eugène Marquis, Rennes: C Dugast; Centre Henri Becquerel, Rouen: A Chevrier, T Frebourg, J Tinat, I Tennevet, A Rossi; Hôpital René Huguenin/Institut Curie, Saint Cloud: C Noguès, L Demange†, E Mouret-Fourme; CHU, Saint-Etienne: F Prieur; Centre Paul Strauss, Strasbourg: J-P Fricker, H Nehme-Schuster; Hôpital Civil, Strasbourg: O Caron, C Maugard; Institut Claudius Regaud, Toulouse: L Gladieff, V Feillel; Hôpital Bretonneau, Tours: I Mortemousque; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: E Luporsi; Hôpital de Bravois, Vandoeuvre-les-Nancy: P Jonveaux; Gustave Roussy, Villejuif: A Chompret†, O Caron).
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Garcia, A., Buisson, M., Damiola, F. et al. Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study. Eur J Hum Genet 24, 1324–1329 (2016). https://doi.org/10.1038/ejhg.2015.284
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DOI: https://doi.org/10.1038/ejhg.2015.284
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