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Martrat G , Maxwell CM , Tominaga E , Porta-de-la-Riva M , Bonifaci N , Gomez-Baldo L , Bogliolo M , Lazaro C , Blanco I , Brunet J , Aguilar H , Fernandez-Rodriguez J , Seal S , Renwick A , Rahman N , Kuhl J , Neveling K , Schindler D , Ramirez MJ , Castella M , Hernandez G , Embrace , Easton DF , Peock S , Cook M , Oliver CT , Frost D , Platte R , Evans DG , Lalloo F , Eeles R , Izatt L , Chu C , Davidson R , Ong KR , Cook J , Douglas F , Hodgson S , Brewer C , Morrison PJ , Porteous M , Peterlongo P , Manoukian S , Peissel B , Zaffaroni D , Roversi G , Barile M , Viel A , Pasini B , Ottini L , Putignano AL , Savarese A , Bernard L , Radice P , Healey S , Spurdle A , Chen X , Beesley J , kConFab , Rookus MA , Verhoef S , Tilanus-Linthorst MA , Vreeswijk MP , Asperen CJ , Bodmer D , Ausems MG , van Os TA , Blok MJ , Meijers-Heijboer HE , Hogervorst FB , Hebon , Goldgar DE , Buys S , John EM , Miron A , Southey M , Daly MB , Bcfr , Swe Brca , Harbst K , Borg A , Rantala J , Barbany-Bustinza G , Ehrencrona H , Stenmark-Askmalm M , Kaufman B , Laitman Y , Milgrom R , Friedman E , Domchek SM , Nathanson KL , Rebbeck TR , Johannsson OT , Couch FJ , Wang X , Fredericksen Z , Cuadras D , Moreno V , Pientka FK , Depping R , Caldes T , Osorio A , Benitez J , Bueren J , Heikkinen T , Nevanlinna H , Hamann U , Torres D , Caligo MA , Godwin AK , Imyanitov EN , Janavicius R , Gemo Study Collaborators , Sinilnikova OM , Stoppa-Lyonnet D , Mazoyer S , Verny-Pierre C , Castera L , de Pauw A , Bignon YJ , Uhrhammer N , Peyrat JP , Vennin P , Ferrer SF , Collonge-Rame MA , Mortemousque I , McGuffog L , Chenevix-Trench G , Pereira-Smith OM , Antoniou AC , Ceron J , Tominaga K , Surralles J , Pujana MA
Exploring the link between MORF4L1 and risk of breast cancer
Breast Cancer Res. 2011 ;13(2) :R40
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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 gamma-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.
Notes
Martrat, Griselda Maxwell, Christopher M Tominaga, Emiko Porta-de-la-Riva, Montserrat Bonifaci, Nuria Gomez-Baldo, Laia Bogliolo, Massimo Lazaro, Conxi Blanco, Ignacio Brunet, Joan Aguilar, Helena Fernandez-Rodriguez, Juana Seal, Sheila Renwick, Anthony Rahman, Nazneen Kuhl, Julia Neveling, Kornelia Schindler, Detlev Ramirez, Maria J Castella, Maria Hernandez, Gonzalo Easton, Douglas F Peock, Susan Cook, Margaret Oliver, Clare T Frost, Debra Platte, Radka Evans, D Gareth Lalloo, Fiona Eeles, Rosalind Izatt, Louise Chu, Carol Davidson, Rosemarie Ong, Kai-Ren Cook, Jackie Douglas, Fiona Hodgson, Shirley Brewer, Carole Morrison, Patrick J Porteous, Mary Peterlongo, Paolo Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Roversi, Gaia Barile, Monica Viel, Alessandra Pasini, Barbara Ottini, Laura Putignano, Anna Laura Savarese, Antonella Bernard, Loris Radice, Paolo Healey, Sue Spurdle, Amanda Chen, Xiaoqing Beesley, Jonathan Rookus, Matti A Verhoef, Senno Tilanus-Linthorst, Madeleine A Vreeswijk, Maaike P Asperen, Christi J Bodmer, Danielle Ausems, Margreet G E M van Os, Theo A Blok, Marinus J Meijers-Heijboer, Hanne E J Hogervorst, Frans B L Goldgar, David E Buys, Saundra John, Esther M Miron, Alexander Southey, Melissa Daly, Mary B Harbst, Katja Borg, Ake Rantala, Johanna Barbany-Bustinza, Gisela Ehrencrona, Hans Stenmark-Askmalm, Marie Kaufman, Bella Laitman, Yael Milgrom, Roni Friedman, Eitan Domchek, Susan M Nathanson, Katherine L Rebbeck, Timothy R Johannsson, Oskar Thor Couch, Fergus J Wang, Xianshu Fredericksen, Zachary Cuadras, Daniel Moreno, Victor Pientka, Friederike K Depping, Reinhard Caldes, Trinidad Osorio, Ana Benitez, Javier Bueren, Juan Heikkinen, Tuomas Nevanlinna, Heli Hamann, Ute Torres, Diana Caligo, Maria Adelaide Godwin, Andrew K Imyanitov, Evgeny N Janavicius, Ramunas Sinilnikova, Olga M Stoppa-Lyonnet, Dominique Mazoyer, Sylvie Verny-Pierre, Carole Castera, Laurent de Pauw, Antoine Bignon, Yves-Jean Uhrhammer, Nancy Peyrat, Jean-Philippe Vennin, Philippe Ferrer, Sandra Fert Collonge-Rame, Marie-Agnes Mortemousque, Isabelle McGuffog, Lesley Chenevix-Trench, Georgia Pereira-Smith, Olivia M Antoniou, Antonis C Ceron, Julian Tominaga, Kaoru Surralles, Jordi Pujana, Miguel Angel eng 10118/Cancer Research UK/United Kingdom 11174/Cancer Research UK/United Kingdom R01 AG032134/AG/NIA NIH HHS/ R01 CA128978/CA/NCI NIH HHS/ Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't England 2011/04/07 06:00 Breast Cancer Res. 2011 Apr 5;13(2):R40. doi: 10.1186/bcr2862.