Exploring the link between MORF4L1 and risk of breast cancer

Griselda Martrat, Christopher A. Maxwell, Emiko Tominaga, Montserrat Porta-de-la-Riva, Nuria Bonifaci, Laia Gomez-Baldo, Massimo Bogliolo, Conxi Lazaro, Ignacio Blanco, Joan Brunet, Helena Aguilar, Juana Fernandez-Rodriguez, Sheila Seal, Anthony Renwick, Nazneen Rahman, Julia Kuehl, Kornelia Neveling, Detlev Schindler, Maria J. Ramirez, Maria CastellaGonzalo Hernandez, Douglas F. Easton, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, Carole Brewer, Patrick J. Morrison, Mary Porteous, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Barbara Pasini, Laura Ottini, Anna Laura Putignano, Antonella Savarese, Loris Bernard, Paolo Radice, Sue Healey, Amanda Spurdle, Xiaoqing Chen, Jonathan Beesley, Matti A. Rookus, Senno Verhoef, Madeleine A. Tilanus-Linthorst, Maaike P. Vreeswijk, Christi J. Asperen, Danielle Bodmer, Margreet G. E. M. Ausems, Theo A. van Os, Marinus J. Blok, Hanne E. J. Meijers-Heijboer, Frans B. L. Hogervorst, David E. Goldgar, Saundra Buys, Esther M. John, Alexander Miron, Melissa Southey, Mary B. Daly, Katja Harbst, Åke Borg, Johanna Rantala, Gisela Barbany-Bustinza, Hans Ehrencrona, Marie Stenmark-Askmalm, Bella Kaufman, Yael Laitman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Oskar Thor Johannsson, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Daniel Cuadras, Vctor Moreno, Friederike K. Pientka, Reinhard Depping, Trinidad Caldes, Ana Osorio, Javier Benitez, Juan Bueren, Tuomas Heikkinen, Heli Nevanlinna, Ute Hamann, Diana Torres, Maria Adelaide Caligo, Andrew K. Godwin, Evgeny N. Imyanitov, Ramunas Janavicius, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine de Pauw, Yves-Jean Bignon, Nancy Uhrhammer, Jean-Philippe Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnes Collonge-Rame, Isabelle Mortemousque, Lesley McGuffog, Georgia Chenevix-Trench, Olivia M. Pereira-Smith, Antonis C. Antoniou, Julian Ceron, Kaoru Tominaga, Jordi Surralles, Miguel Angel Pujana

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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 g-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, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 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.
Original languageEnglish
Article numberR40
JournalBreast Cancer Research
Issue number2
Publication statusPublished - 2011

Subject classification (UKÄ)

  • Cancer and Oncology

Free keywords

  • Rad51 Recombinase
  • RNA Interference
  • Nuclear Proteins
  • Mutation
  • Mice
  • Humans
  • Genetic Predisposition to Disease
  • BRCA2
  • BRCA1
  • Genes
  • Female
  • Fanconi Anemia Complementation Group D2 Protein
  • Fanconi Anemia
  • DNA Repair
  • DNA Damage
  • Cell Line
  • Caenorhabditis elegans
  • Animals
  • Breast Neoplasms
  • Replication Protein A
  • Risk Factors
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Two-Hybrid System Techniques


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