Épidémiologie génétique des cancers

Publications de l’équipe

Année de publication : 2017

Mathurin Dorel, Eric Viara, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein (2017 Apr 18)

NaviCom: a web application to create interactive molecular network portraits using multi-level omics data.

Database : the journal of biological databases and curation : DOI : 10.1093/database/bax026 En savoir plus
Résumé

Human diseases such as cancer are routinely characterized by high-throughput molecular technologies, and multi-level omics data are accumulated in public databases at increasing rate. Retrieval and visualization of these data in the context of molecular network maps can provide insights into the pattern of regulation of molecular functions reflected by an omics profile. In order to make this task easy, we developed NaviCom, a Python package and web platform for visualization of multi-level omics data on top of biological network maps. NaviCom is bridging the gap between cBioPortal, the most used resource of large-scale cancer omics data and NaviCell, a data visualization web service that contains several molecular network map collections. NaviCom proposes several standardized modes of data display on top of molecular network maps, allowing addressing specific biological questions. We illustrate how users can easily create interactive network-based cancer molecular portraits via NaviCom web interface using the maps of Atlas of Cancer Signalling Network (ACSN) and other maps. Analysis of these molecular portraits can help in formulating a scientific hypothesis on the molecular mechanisms deregulated in the studied disease.

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Laura Cantini, Michele Caselle, Antoine Forget, Andrei Zinovyev, Emmanuel Barillot, Loredana Martignetti (2017 Apr 15)

A review of computational approaches detecting microRNAs involved in cancer.

Frontiers in bioscience (Landmark edition) : 1774-1791 En savoir plus
Résumé

MicroRNAs (miRNAs) are small non-coding RNAs playing an essential role in gene expression regulation. Multiple studies have demonstrated that miRNAs are dysregulated in cancer initiation and progression, pointing out their potential as biomarkers for diagnosis, prognosis and response to treatment. With the introduction of high-throughput technologies several computational approaches have been proposed to identify cancer-associated miRNAs. Here, we present a systematic and comprehensive overview of the current knowledge concerning the computational detection of miRNAs involved in tumor onset and subtyping, with possible theranostic employment. An overview of the state of art in this field is thus proposed with the aim of supporting researchers, especially experimentalists and pathologists, in choosing the optimal approach for their case of study.

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Catherine M Phelan, Karoline B Kuchenbaecker, Jonathan P Tyrer, Siddhartha P Kar, Kate Lawrenson, Stacey J Winham, Joe Dennis, Ailith Pirie, Marjorie J Riggan, Ganna Chornokur, Madalene A Earp, Paulo C Lyra, Janet M Lee, Simon Coetzee, Jonathan Beesley, Lesley McGuffog, Penny Soucy, Ed Dicks, Andrew Lee, Daniel Barrowdale, Julie Lecarpentier, Goska Leslie, Cora M Aalfs, Katja K H Aben, Marcia Adams, Julian Adlard, Irene L Andrulis, Hoda Anton-Culver, Natalia Antonenkova, , Gerasimos Aravantinos, Norbert Arnold, Banu K Arun, Brita Arver, Jacopo Azzollini, Judith Balmaña, Susana N Banerjee, Laure Barjhoux, Rosa B Barkardottir, Yukie Bean, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Marcus Q Bernardini, Michael J Birrer, Line Bjorge, Amanda Black, Kenneth Blankstein, Marinus J Blok, Clara Bodelon, Natalia Bogdanova, Anders Bojesen, Bernardo Bonanni, Åke Borg, Angela R Bradbury, James D Brenton, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Fiona Bruinsma, Joan Brunet, Bruno Buecher, Ralf Butzow, Saundra S Buys, Trinidad Caldes, Maria A Caligo, Ian Campbell, Rikki Cannioto, Michael E Carney, Terence Cescon, Salina B Chan, Jenny Chang-Claude, Stephen Chanock, Xiao Qing Chen, Yoke-Eng Chiew, Jocelyne Chiquette, Wendy K Chung, Kathleen B M Claes, Thomas Conner, Linda S Cook, Jackie Cook, Daniel W Cramer, Julie M Cunningham, Aimee A D'Aloisio, Mary B Daly, Francesca Damiola, Sakaeva Dina Damirovna, Agnieszka Dansonka-Mieszkowska, Fanny Dao, Rosemarie Davidson, Anna DeFazio, Capucine Delnatte, Kimberly F Doheny, Orland Diez, Yuan Chun Ding, Jennifer Anne Doherty, Susan M Domchek, Cecilia M Dorfling, Thilo Dörk, Laure Dossus, Mercedes Duran, Matthias Dürst, Bernd Dworniczak, Diana Eccles, Todd Edwards, Ros Eeles, Ursula Eilber, Bent Ejlertsen, Arif B Ekici, Steve Ellis, Mingajeva Elvira, , Kevin H Eng, Christoph Engel, D Gareth Evans, Peter A Fasching, Sarah Ferguson, Sandra Fert Ferrer, James M Flanagan, Zachary C Fogarty, Renée T Fortner, Florentia Fostira, William D Foulkes, George Fountzilas, Brooke L Fridley, Tara M Friebel, Eitan Friedman, Debra Frost, Patricia A Ganz, Judy Garber, María J García, Vanesa Garcia-Barberan, Andrea Gehrig, , Aleksandra Gentry-Maharaj, Anne-Marie Gerdes, Graham G Giles, Rosalind Glasspool, Gord Glendon, Andrew K Godwin, David E Goldgar, Teodora Goranova, Martin Gore, Mark H Greene, Jacek Gronwald, Stephen Gruber, Eric Hahnen, Christopher A Haiman, Niclas Håkansson, Ute Hamann, Thomas V O Hansen, Patricia A Harrington, Holly R Harris, Jan Hauke, , Alexander Hein, Alex Henderson, Michelle A T Hildebrandt, Peter Hillemanns, Shirley Hodgson, Claus K Høgdall, Estrid Høgdall, Frans B L Hogervorst, Helene Holland, Maartje J Hooning, Karen Hosking, Ruea-Yea Huang, Peter J Hulick, Jillian Hung, David J Hunter, David G Huntsman, Tomasz Huzarski, Evgeny N Imyanitov, Claudine Isaacs, Edwin S Iversen, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Mats Jernetz, Allan Jensen, Uffe Birk Jensen, Esther M John, Sharon Johnatty, Michael E Jones, Päivi Kannisto, Beth Y Karlan, Anthony Karnezis, Karin Kast, , Catherine J Kennedy, Elza Khusnutdinova, Lambertus A Kiemeney, Johanna I Kiiski, Sung-Won Kim, Susanne K Kjaer, Martin Köbel, Reidun K Kopperud, Torben A Kruse, Jolanta Kupryjanczyk, Ava Kwong, Yael Laitman, Diether Lambrechts, Nerea Larrañaga, Melissa C Larson, Conxi Lazaro, Nhu D Le, Loic Le Marchand, Jong Won Lee, Shashikant B Lele, Arto Leminen, Dominique Leroux, Jenny Lester, Fabienne Lesueur, Douglas A Levine, Dong Liang, Clemens Liebrich, Jenna Lilyquist, Loren Lipworth, Jolanta Lissowska, Karen H Lu, Jan Lubinński, Craig Luccarini, Lene Lundvall, Phuong L Mai, Gustavo Mendoza-Fandiño, Siranoush Manoukian, Leon F A G Massuger, Taymaa May, Sylvie Mazoyer, Jessica N McAlpine, Valerie McGuire, John R McLaughlin, Iain McNeish, Hanne Meijers-Heijboer, Alfons Meindl, Usha Menon, Arjen R Mensenkamp, Melissa A Merritt, Roger L Milne, Gillian Mitchell, Francesmary Modugno, Joanna Moes-Sosnowska, Melissa Moffitt, Marco Montagna, Kirsten B Moysich, Anna Marie Mulligan, Jacob Musinsky, Katherine L Nathanson, Lotte Nedergaard, Roberta B Ness, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Robert L Nussbaum, Kunle Odunsi, Edith Olah, Olufunmilayo I Olopade, Håkan Olsson, Curtis Olswold, David M O'Malley, Kai-Ren Ong, N Charlotte Onland-Moret, , Nicholas Orr, Sandra Orsulic, Ana Osorio, Domenico Palli, Laura Papi, Tjoung-Won Park-Simon, James Paul, Celeste L Pearce, Inge Søkilde Pedersen, Petra H M Peeters, Bernard Peissel, Ana Peixoto, Tanja Pejovic, Liisa M Pelttari, Jennifer B Permuth, Paolo Peterlongo, Lidia Pezzani, Georg Pfeiler, Kelly-Anne Phillips, Marion Piedmonte, Malcolm C Pike, Anna M Piskorz, Samantha R Poblete, Timea Pocza, Elizabeth M Poole, Bruce Poppe, Mary E Porteous, Fabienne Prieur, Darya Prokofyeva, Elizabeth Pugh, Miquel Angel Pujana, Pascal Pujol, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Kerstin Rhiem, Patricia Rice, Andrea Richardson, Mark Robson, Gustavo C Rodriguez, Cristina Rodríguez-Antona, Jane Romm, Matti A Rookus, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Helga B Salvesen, Dale P Sandler, Minouk J Schoemaker, Leigha Senter, V Wendy Setiawan, Gianluca Severi, Priyanka Sharma, Tameka Shelford, Nadeem Siddiqui, Lucy E Side, Weiva Sieh, Christian F Singer, Hagay Sobol, Honglin Song, Melissa C Southey, Amanda B Spurdle, Zsofia Stadler, Doris Steinemann, Dominique Stoppa-Lyonnet, Lara E Sucheston-Campbell, Grzegorz Sukiennicki, Rebecca Sutphen, Christian Sutter, Anthony J Swerdlow, Csilla I Szabo, Lukasz Szafron, Yen Y Tan, Jack A Taylor, Muy-Kheng Tea, Manuel R Teixeira, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Liv Cecilie Vestrheim Thomsen, Darcy L Thull, Laima Tihomirova, Anna V Tinker, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Alicia Tone, Britton Trabert, Ruth C Travis, Antonia Trichopoulou, Nadine Tung, Shelley S Tworoger, Anne M van Altena, David Van Den Berg, Annemarie H van der Hout, Rob B van der Luijt, Mattias Van Heetvelde, Els Van Nieuwenhuysen, Elizabeth J van Rensburg, Adriaan Vanderstichele, Raymonda Varon-Mateeva, Ana Vega, Digna Velez Edwards, Ignace Vergote, Robert A Vierkant, Joseph Vijai, Athanassios Vratimos, Lisa Walker, Christine Walsh, Dorothea Wand, Shan Wang-Gohrke, Barbara Wappenschmidt, Penelope M Webb, Clarice R Weinberg, Jeffrey N Weitzel, Nicolas Wentzensen, Alice S Whittemore, Juul T Wijnen, Lynne R Wilkens, Alicja Wolk, Michelle Woo, Xifeng Wu, Anna H Wu, Hannah Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Kristin K Zorn, Steven A Narod, Douglas F Easton, Christopher I Amos, Joellen M Schildkraut, Susan J Ramus, Laura Ottini, Marc T Goodman, Sue K Park, Linda E Kelemen, Harvey A Risch, Mads Thomassen, Kenneth Offit, Jacques Simard, Rita Katharina Schmutzler, Dennis Hazelett, Alvaro N Monteiro, Fergus J Couch, Andrew Berchuck, Georgia Chenevix-Trench, Ellen L Goode, Thomas A Sellers, Simon A Gayther, Antonis C Antoniou, Paul D P Pharoah (2017 Mar 28)

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nature genetics : DOI : 10.1038/ng.3826 En savoir plus
Résumé

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

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Haitham Ashoor, Caroline Louis-Brennetot, Isabelle Janoueix-Lerosey, Vladimir B Bajic, Valentina Boeva (2017 Jan 6)

HMCan-diff: a method to detect changes in histone modifications in cells with different genetic characteristics.

Nucleic acids research : DOI : gkw1319 En savoir plus
Résumé

Comparing histone modification profiles between cancer and normal states, or across different tumor samples, can provide insights into understanding cancer initiation, progression and response to therapy. ChIP-seq histone modification data of cancer samples are distorted by copy number variation innate to any cancer cell. We present HMCan-diff, the first method designed to analyze ChIP-seq data to detect changes in histone modifications between two cancer samples of different genetic backgrounds, or between a cancer sample and a normal control. HMCan-diff explicitly corrects for copy number bias, and for other biases in the ChIP-seq data, which significantly improves prediction accuracy compared to methods that do not consider such corrections. On in silico simulated ChIP-seq data generated using genomes with differences in copy number profiles, HMCan-diff shows a much better performance compared to other methods that have no correction for copy number bias. Additionally, we benchmarked HMCan-diff on four experimental datasets, characterizing two histone marks in two different scenarios. We correlated changes in histone modifications between a cancer and a normal control sample with changes in gene expression. On all experimental datasets, HMCan-diff demonstrated better performance compared to the other methods.

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Année de publication : 2016

A N Gorban, E M Mirkes, A Zinovyev (2016 Sep 19)

Piece-wise quadratic approximations of arbitrary error functions for fast and robust machine learning.

Neural networks : the official journal of the International Neural Network Society : 28-38 : DOI : S0893-6080(16)30111-3 En savoir plus
Résumé

Most of machine learning approaches have stemmed from the application of minimizing the mean squared distance principle, based on the computationally efficient quadratic optimization methods. However, when faced with high-dimensional and noisy data, the quadratic error functionals demonstrated many weaknesses including high sensitivity to contaminating factors and dimensionality curse. Therefore, a lot of recent applications in machine learning exploited properties of non-quadratic error functionals based on L1 norm or even sub-linear potentials corresponding to quasinorms Lp (0 Replier

Yan Ren, Juan Jesus Lence-Anta, Celia Pereda, Mae Chappa, Milagro Velasco, Idalmis Infante, Marlene Bustillo, Sylvia Turcios, Axelle Leufroy, Thierry Guérin, Laurent Noël, Fabienne Lesueur, Stéphane Maillard, Ernora Clero, Constance Xhaard, Rodrigue S Allodji, Carole Rubino, Regla Rodriguez, Rosa Ortiz, Florent de Vathaire (2016 Sep 10)

Foxe1 Polymorphism Interacts with Dietary Iodine Intake in Differentiated Thyroid Cancer Risk in the Cuban Population.

Thyroid : official journal of the American Thyroid Association En savoir plus
Résumé

The incidence of differentiated thyroid cancer (DTC) is low in Cuba and the contribution of dietary factors to DTC in this population has not been investigated so far. Our aim was to evaluate the relationship between dietary iodine intake and DTC with regard to the interaction with environmental factors or some common single nucleotide polymorphisms (SNPs), based on a case-control study carried out in Cuba.

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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 En savoir plus
Résumé

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.

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Heinrich Kovar, James Amatruda, Erika Brunet, Stefan Burdach, Florencia Cidre-Aranaz, Enrique de Alava, Uta Dirksen, Wietske van der Ent, Patrick Grohar, Thomas G P Grünewald, Lee Helman, Peter Houghton, Kristiina Iljin, Eberhard Korsching, Marc Ladanyi, Elizabeth Lawlor, Stephen Lessnick, Joseph Ludwig, Paul Meltzer, Markus Metzler, Jaume Mora, Richard Moriggl, Takuro Nakamura, Theodore Papamarkou, Branka Radic Sarikas, Francoise Rédini, Guenther H S Richter, Claudia Rossig, Keri Schadler, Beat W Schäfer, Katia Scotlandi, Nathan C Sheffield, Anang Shelat, Ewa Snaar-Jagalska, Poul Sorensen, Kimberly Stegmaier, Elizabeth Stewart, Alejandro Sweet-Cordero, Karoly Szuhai, Oscar M Tirado, Franck Tirode, Jeffrey Toretsky, Kalliopi Tsafou, Aykut Üren, Andrei Zinovyev, Olivier Delattre (2016 Jan 24)

The second European interdisciplinary Ewing sarcoma research summit – A joint effort to deconstructing the multiple layers of a complex disease.

Oncotarget : 8613-24 : DOI : 10.18632/oncotarget.6937 En savoir plus
Résumé

Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second « European interdisciplinary Ewing sarcoma research summit » assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.

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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 En savoir plus
Résumé

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.European Journal of Human Genetics advance online publication, 20 January 2016; doi:10.1038/ejhg.2015.284.

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Tatiana Popova, Elodie Manié, Valentina Boeva, Aude Battistella, Oumou Goundiam, Nicholas K Smith, Christopher R Mueller, Virginie Raynal, Odette Mariani, Xavier Sastre-Garau, Marc-Henri Stern (2016 Jan 21)

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications.

Cancer research : 1882-91 : DOI : 10.1158/0008-5472.CAN-15-2128 En savoir plus
Résumé

CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal (∼0.3 and ∼3 Mb) size distribution and overlapping microhomology at the breakpoints. This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis. Cancer Res; 76(7); 1882-91. ©2016 AACR.

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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 Gauthier-Villars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Catherine Dugast, Paul Gesta, Jean-Pierre 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 Fert-Ferrer, Clotilde Penet, Thierry Frebourg, Marie-Agnès Collonge-Rame, Emmanuelle Barouk-Simonet, 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 En savoir plus
Résumé

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.

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Année de 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 En savoir plus
Résumé

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 in-frame 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.

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Matahi Moarii, Valentina Boeva, Jean-Philippe Vert, Fabien Reyal (2015 Oct 30)

Changes in correlation between promoter methylation and gene expression in cancer.

BMC genomics : 873 : DOI : 10.1186/s12864-015-1994-2 En savoir plus
Résumé

Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation. Aberrant promoter methylation is considered a hallmark of cancer involved in silencing of tumor suppressor genes and activation of oncogenes. However, recent studies have also challenged the simple model of gene expression control by promoter methylation in cancer, and the precise mechanism of and role played by changes in DNA methylation in carcinogenesis remains elusive.

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Sophie Blein, Laure Barjhoux, , Francesca Damiola, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Morgane Marcou, Olivier Caron, Alain Lortholary, Bruno Buecher, Philippe Vennin, Pascaline Berthet, Catherine Noguès, Christine Lasset, Marion Gauthier-Villars, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Nadine Andrieu, Gilles Thomas, Olga M Sinilnikova, David G Cox (2015 Sep 26)

Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.

PloS one : e0136192 : DOI : 10.1371/journal.pone.0136192 En savoir plus
Résumé

Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.

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I Kuperstein, E Bonnet, H-A Nguyen, D Cohen, E Viara, L Grieco, S Fourquet, L Calzone, C Russo, M Kondratova, M Dutreix, E Barillot, A Zinovyev (2015 Jul 21)

Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps.

Oncogenesis : e160 : DOI : 10.1038/oncsis.2015.19 En savoir plus
Résumé

Cancerogenesis is driven by mutations leading to aberrant functioning of a complex network of molecular interactions and simultaneously affecting multiple cellular functions. Therefore, the successful application of bioinformatics and systems biology methods for analysis of high-throughput data in cancer research heavily depends on availability of global and detailed reconstructions of signalling networks amenable for computational analysis. We present here the Atlas of Cancer Signalling Network (ACSN), an interactive and comprehensive map of molecular mechanisms implicated in cancer. The resource includes tools for map navigation, visualization and analysis of molecular data in the context of signalling network maps. Constructing and updating ACSN involves careful manual curation of molecular biology literature and participation of experts in the corresponding fields. The cancer-oriented content of ACSN is completely original and covers major mechanisms involved in cancer progression, including DNA repair, cell survival, apoptosis, cell cycle, EMT and cell motility. Cell signalling mechanisms are depicted in detail, together creating a seamless ‘geographic-like’ map of molecular interactions frequently deregulated in cancer. The map is browsable using NaviCell web interface using the Google Maps engine and semantic zooming principle. The associated web-blog provides a forum for commenting and curating the ACSN content. ACSN allows uploading heterogeneous omics data from users on top of the maps for visualization and performing functional analyses. We suggest several scenarios for ACSN application in cancer research, particularly for visualizing high-throughput data, starting from small interfering RNA-based screening results or mutation frequencies to innovative ways of exploring transcriptomes and phosphoproteomes. Integration and analysis of these data in the context of ACSN may help interpret their biological significance and formulate mechanistic hypotheses. ACSN may also support patient stratification, prediction of treatment response and resistance to cancer drugs, as well as design of novel treatment strategies.

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