Publications de l’équipe Génomique et biologie des cancers du sein héréditaires Année de publication : 2012 Tatiana Popova, Elodie Manié, Guillaume Rieunier, Virginie Caux-Moncoutier, Carole Tirapo, Thierry Dubois, Olivier Delattre, Brigitte Sigal-Zafrani, Marc Bollet, Michel Longy, Claude Houdayer, Xavier Sastre-Garau, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Marc-Henri Stern (2012 Aug 29) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer research : 5454-62 : DOI : 10.1158/0008-5472.CAN-12-1470 Résumé BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Largescale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. Jordan Madic, Sophie Piperno-Neumann, Vincent Servois, Aurore Rampanou, Maud Milder, Bénédicte Trouiller, David Gentien, Stéphanie Saada, Franck Assayag, Aurélie Thuleau, Fariba Nemati, Didier Decaudin, François-Clément Bidard, Laurence Desjardins, Pascale Mariani, Olivier Lantz, Marc-Henri Stern (2012 May 29) Pyrophosphorolysis-activated polymerization detects circulating tumor DNA in metastatic uveal melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research : 3934-41 : DOI : 10.1158/1078-0432.CCR-12-0309 Résumé To develop a molecular tool to detect circulating tumor-derived DNA (ctDNA) in the plasma from patients with uveal melanoma as a marker of tumor burden and monitor treatment efficacy. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Publications de l’équipe Génomique et biologie des cancers du sein héréditaires Année de publication : 2011 Virginie Jacquemin, Guillaume Rieunier, Sandrine Jacob, Dorine Bellanger, Catherine Dubois d'Enghien, Anthony Laugé, Dominique Stoppa-Lyonnet, Marc-Henri Stern (2011 Nov 11) Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. European journal of human genetics : EJHG : 305-12 : DOI : 10.1038/ejhg.2011.196 Résumé Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T. Année de publication : 2010 Julien Bouley, Cédric Pionneau, Justine Varinot, Denis Biard, Catherine Genestie, Martine Antoine, Florence Coulet, Marc-Henri Stern, Dominique Stoppa-Lyonnet, Florent Soubrier (2010 Dec 8) Proteomic analysis of BRCA1-depleted cell line reveals a putative role for replication protein A2 up-regulation in BRCA1 breast tumor development. Proteomics. Clinical applications : 489-98 : DOI : 10.1002/prca.200900107 Résumé Germline mutations in BRCA1 result in a strong predisposition to breast cancer, with frequent loss of heterozygosity of the remaining wild-type allele. The development of BRCA1 tumors is likely to depend on additional genetic alterations and gene expression changes which follow growth and DNA repair defects associated with BRCA1 deficiency. The identification of these modifications offers an opportunity to find surrogate markers of BRCA1 tumors. Here, we sought to identify differentially expressed proteins related to BRCA1 depletion. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Publications de l’équipe Génomique et biologie des cancers du sein héréditaires INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3