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Team Publications Genetic Epidemiology of Cancer Year of publication 2016 Cécile Boscheron, Fabrice Caudron, Sophie Loeillet, Charlotte Peloso, Marine Mugnier, Laetitia Kurzawa, Alain Nicolas, Eric Denarier, Laurence Aubry, Annie Andrieux (2016 Jul 29) A role for the microtubule +end protein Bik1 (CLIP170) and the Rho1 GTPase in Snc1 trafficking. Journal of cell science : DOI : jcs.190330 Summary The diversity of microtubule functions is dependent on the status of tubulin C-termini. To address the physiological role of the C-terminal aromatic residue of α-tubulin, a tub1-Glu yeast strain expressing an α-tubulin devoid of its C-terminal amino-acid was used to perform a genome-wide-lethality screen. The identified synthetic lethal genes suggested links with endocytosis and related processes. In the tub1-Glu strain, the routing of the v-SNARE Snc1 was strongly impaired, with a loss of its polarized distribution in the bud and Abp1, an actin patch/endocytic marker, developed comet-tails structures. Snc1 trafficking necessitated dynamic microtubules but not dynein and kinesin motors. Interestingly, deletion of the microtubule +end protein Bik1 (CLIP170), which is preferentially recruited to the C-terminal residue of α-tubulin, similarly resulted in Snc1 trafficking defects. Finally, constitutively active Rho1 rescued both Bik1 localization at microtubule +ends in tub1-Glu strain and a correct Snc1 trafficking in a Bik1-dependent manner. Our results provide the first evidence for a role of microtubule +ends in membrane-cargo trafficking in yeast, through Rho1- and Bik1-dependent mechanisms and highlight the importance of α-tubulin last amino-acid in this process. Amandine I Garcia, Monique Buisson, Francesca Damiola, Chloé Tessereau, Laure Barjhoux, Carole Verny-Pierre, Valérie Sornin, Marie-Gabrielle Dondon, Séverine Eon-Marchais, , Olivier Caron, Marion Gautier-Villars, Isabelle Coupier, Bruno Buecher, Philippe Vennin, Muriel Belotti, Alain Lortholary, Paul Gesta, Catherine Dugast, Catherine Noguès, Jean-Pierre Fricker, Laurence Faivre, Dominique Stoppa-Lyonnet, Nadine Andrieu, Olga M Sinilnikova, Sylvie Mazoyer (2016 Jan 21) Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study. European journal of human genetics : EJHG : DOI : 10.1038/ejhg.2015.284 Summary 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 INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications Genetic Epidemiology of Cancer 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.European Journal of Human Genetics advance online publication, 20 January 2016; doi:10.1038/ejhg.2015.284. Olga M Sinilnikova, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Francesca Damiola, Laure Barjhoux, Morgane Marcou, Carole Verny-Pierre, Valérie Sornin, Lucie Toulemonde, Juana Beauvallet, Dorothée Le Gal, Noura Mebirouk, Muriel Belotti, Olivier Caron, Marion GauthierVillars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Catherine Dugast, Paul Gesta, JeanPierre Fricker, Catherine Noguès, Laurence Faivre, Elisabeth Luporsi, Pascaline Berthet, Capucine Delnatte, Valérie Bonadona, Christine M Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Claude Adenis, Laurence Venat-Bouvet, Liliane Demange, Hélène Dreyfus, Marc Frenay, Laurence Gladieff, Isabelle Mortemousque, Séverine Audebert-Bellanger, Florent Soubrier, Sophie Giraud, Sophie Lejeune-Dumoulin, Annie Chevrier, Jean-Marc Limacher, Jean Chiesa, Anne Fajac, Anne Floquet, François Eisinger, Julie Tinat, Chrystelle Colas, Sandra FertFerrer, Clotilde Penet, Thierry Frebourg, Marie-Agnès Collonge-Rame, Emmanuelle BaroukSimonet, Valérie Layet, Dominique Leroux, Odile Cohen-Haguenauer, Fabienne Prieur, Emmanuelle Mouret-Fourme, François Cornélis, Philippe Jonveaux, Odile Bera, Eve Cavaciuti, Anne Tardivon, Fabienne Lesueur, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Nadine Andrieu (2016 Jan 14) GENESIS: a French national resource to study the missing heritability of breast cancer. BMC cancer : 13 : DOI : 10.1186/s12885-015-2028-9 Summary Less than 20% of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications Genetic Epidemiology of Cancer Year of publication 2015 Francesca Damiola, Inès Schultz, Laure Barjhoux, Valérie Sornin, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Morgane Marcou, , Olivier Caron, Marion Gauthier-Villars, Antoine de Pauw, Elisabeth Luporsi, Pascaline Berthet, Capucine Delnatte, Valérie Bonadona, Christine Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Jean-Pierre Fricker, Nadine Andrieu, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Danièle Muller (2015 Nov 14) Mutation analysis of PALB2 gene in French breast cancer families. Breast cancer research and treatment : 463-71 : DOI : 10.1007/s10549-015-3625-7 Summary Several population-based and family-based studies have demonstrated that germline mutations of the PALB2 gene (Partner and Localizer of BRCA2) are associated with an increased risk of breast cancer. Distinct mutation frequencies and spectrums have been described depending on the population studied. Here we describe the first complete PALB2 coding sequence screening in the French population. We screened the complete coding sequence and intron-exon boundaries of PALB2, using the EMMA technique, to assess the contribution of pathogenic mutations in a set of 835 familial breast cancer cases and 662 unrelated controls from the French national study GENESIS and the Paul Strauss Cancer Centre, all previously tested negative for BRCA1 and BRCA2 pathogenic mutations. Our analysis revealed the presence of four novel deleterious mutations: c.1186insT, c.1857delT and c.2850delC in three cases, c.3418dupT in one control. In addition, we identified two inframe insertion/deletion, 19 missense substitutions (two of them predicted as pathogenic), 9 synonymous variants, 28 variants located in introns and 2 in UTRs, as well as frequent variants. Truncating PALB2 mutations were found in 0.36% of familial breast cancer cases, a frequency lower than the one detected in comparable studies in other populations (0.73-3.40%). This suggests a small but significant contribution of PALB2 mutations to the breast cancer susceptibility in the French population. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3