title: Mutation screening of MIR146A/B and BRCA1/2 3'-UTRs in the GENESIS study.
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.
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Amandine I
authors.initials: AI
authors.lastname: Garcia
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Buisson
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Damiola
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Tessereau
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Barjhoux
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Verny-Pierre
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Sornin
authors.affiliation: INSERM, U900, Paris, France.|Institut Curie, Paris, France.|Mines ParisTech, Fontainebleau, France.
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Dondon
authors.affiliation: INSERM, U900, Paris, France.|Institut Curie, Paris, France.|Mines ParisTech, Fontainebleau, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Eon-Marchais
authors.affiliation: Département de Médecine Oncologique, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.affiliation: Institut Curie, Service de Génétique, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gautier-Villars
authors.affiliation: Hôpital Arnaud de Villeneuve, CHU Montpellier, Service de Génétique médicale et Oncogénétique, Montpellier, France.|ICM Val d'Aurel, Unité d'Oncogénétique, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.affiliation: Institut Curie, Service de Génétique, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Buecher
authors.affiliation: Centre Oscar Lambret, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vennin
authors.affiliation: Institut Curie, Service de Génétique, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Belotti
authors.affiliation: Centre Catherine de Sienne, Service d'Oncologie Médicale, Nantes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.affiliation: CH Georges Renon, Service Oncogénétique pour la consultation oncogénétique régionale Poitou-Charentes, Niort, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Gesta
authors.affiliation: Centre Eugène Marquis, Service de Génétique, Rennes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dugast
authors.affiliation: Institut Curie, Service de Génétique, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Noguès
authors.affiliation: Centre Paul Strauss, Unité d'Oncologie, Strasbourg, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fricker
authors.affiliation: Hôpital d'Enfants, Service de Génétique Médicale, Dijon, France.|Centre Georges François Leclerc, Oncogénétique, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Institut Curie, Service de Génétique, Paris, France.|Inserm, U830, Université Paris-Descartes, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: INSERM, U900, Paris, France.|Institut Curie, Paris, France.|Mines ParisTech, Fontainebleau, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrieu
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.|Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.affiliation: Cancer Research Centre of Lyon, CNRS UMR5286/Inserm U1052/Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation
chemical_list: D020413:3' Untranslated Regions; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs