Exploring the link between MORF4L1 and risk of breast cancer.

Griselda Martrat 1, 2 Christopher Maxwell 1, 2 Emiko Tominaga 3 Montserrat Porta-De-La-Riva 4 Núria Bonifaci 2, 5 Laia Gómez-Baldó 1, 2 Massimo Bogliolo 6, 7 Conxi Lázaro 8 Ignacio Blanco 8 Joan Brunet 8 Helena Aguilar 1 Juana Fernández-Rodríguez 8 Sheila Seal 9 Anthony Renwick 9 Nazneen Rahman 9 Julia Kühl 10 Kornelia Neveling 10 Detlev Schindler 10 María Ramírez 6, 7 María Castellà 6, 7 Gonzalo Hernández 6, 7 Douglas Easton 11 Susan Peock 11 Margaret Cook 11 Clare Oliver 11 Debra Frost 11 Radka Platte 12 D Gareth Evans 13 Fiona Lalloo 13 Rosalind Eeles 14 Louise Izatt 15 Carol Chu 16 Rosemarie Davidson 17 Kai-Ren Ong 18 Jackie Cook 19 Fiona Douglas 20 Shirley Hodgson 21 Carole Brewer 22 Patrick Morrison 23 Mary Porteous 24 Paolo Peterlongo 25, 26 Siranoush Manoukian 27 Bernard Peissel 27 Daniela Zaffaroni 27 Gaia Roversi 27 Monica Barile 28 Alessandra Viel 29 Barbara Pasini 30 Laura Ottini 31 Anna Putignano 32, 33 Antonella Savarese 34 Loris Bernard 35 Paolo Radice 25, 26 Sue Healey 36 Amanda Spurdle 36 Xiaoqing Chen 36 Jonathan Beesley 36 Matti Rookus 37 Senno Verhoef 38 Madeleine Tilanus-Linthorst 39 Maaike Vreeswijk 40 Christi Asperen 40 Danielle Bodmer 41 Margreet Ausems 42 Theo Van Os 43 Marinus Blok 44 Hanne Meijers-Heijboer 45 Frans Hogervorst 38 David Goldgar 46 Saundra Buys 47 Esther John 48 Alexander Miron 49, 50 Melissa Southey 51 Mary Daly 52 Katja Harbst 53 Åke Borg 53 Johanna Rantala 54 Gisela Barbany-Bustinza 54 Hans Ehrencrona 55 Marie Stenmark-Askmalm 56 Bella Kaufman 57 Yael Laitman 58 Roni Milgrom 58 Eitan Friedman 58, 59 Susan Domchek 60 Katherine Nathanson 61 Timothy Rebbeck 62 Oskar Johannsson 63, 64 Fergus Couch 65, 66 Xianshu Wang 65 Zachary Fredericksen 66 Daniel Cuadras 67 Víctor Moreno 2, 5 Friederike Pientka 68 Reinhard Depping 68 Trinidad Caldés 69 Ana Osorio 70 Javier Benítez 70 Juan Bueren 71 Tuomas Heikkinen 72 Heli Nevanlinna 72 Ute Hamann 73 Diana Torres 74 Maria Caligo 75 Andrew Godwin 76 Evgeny Imyanitov 77 Ramunas Janavicius 78 Olga Sinilnikova 79, 80 Dominique Stoppa-Lyonnet 81, 82 Sylvie Mazoyer 80 Carole Verny-Pierre 80 Laurent Castera 81 Antoine De Pauw 81 Yves-Jean Bignon 83 Nancy Uhrhammer 83 Jean-Philippe Peyrat 84 Philippe Vennin 85 Sandra Ferrer 86 Marie-Agnès Collonge-Rame 87 Isabelle Mortemousque 88 Lesley Mcguffog 11 Georgia Chenevix-Trench 36 Olivia Pereira-Smith 3 Antonis Antoniou 11 Julián Cerón 4, * Kaoru Tominaga 3, * Jordi Surrallés 6, 7, * Miguel Pujana 1, 2, 5, *
* Auteur correspondant
Abstract : ABSTRACT: INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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Article dans une revue
Breast Cancer Research, BioMed Central, 2011, 13 (2), pp.R40. 〈10.1186/bcr2862〉
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http://www.hal.inserm.fr/inserm-00622815
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Soumis le : lundi 12 septembre 2011 - 17:04:54
Dernière modification le : dimanche 6 mai 2018 - 01:19:01
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Griselda Martrat, Christopher Maxwell, Emiko Tominaga, Montserrat Porta-De-La-Riva, Núria Bonifaci, et al.. Exploring the link between MORF4L1 and risk of breast cancer.. Breast Cancer Research, BioMed Central, 2011, 13 (2), pp.R40. 〈10.1186/bcr2862〉. 〈inserm-00622815〉

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