Exploring the link between MORF4L1 and risk of breast cancer

Summary, in English

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.

• Author: 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 Castella; Gonzalo 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
• Department/s: Breastcancer-genetics; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
• Publishing year: 2011
• Language: English
• Publication/Series: Breast Cancer Research
• Volume: 13
• Issue: 2
• Full text: - 3 MB; Download statistics
• Links: http://dx.doi.org/10.1186/bcr2862; http://www.ncbi.nlm.nih.gov/pubmed/21466675; http://dx.doi.org/10.1186/bcr2862
• Document type: Journal article
• Publisher: BioMed Central (BMC)
• Topic: Cancer and Oncology
• 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
• Status: Published
• ISBN/ISSN/Other: ISSN: 1465-5411