Exploring the link between MORF4L1 and risk of breast cancer

G. Martrat, C.A. Maxwell, E. Tominaga, M. Porta-de-la-Riva, N. Bonifaci, L. Gomez-Baldo, M. Bogliolo, C. Lázaro, I. Blanco, J. Brunet, H. Aguilar, J. Fernandez-Rodriguez, S. Seal, A. Renwick, N. Rahman, J. Kuehl, K. Neveling, D. Schindler, M.J. Ramirez, M. CastellaG. Hernandez, D.F. Easton, S. Peock, M. Cook, C.T. Oliver, D. Frost, R. Platte, D.G. Evans, F. Lalloo, R. Eeles, L. Izatt, C. Chu, R. Davidson, K.R. Ong, J. Cook, F. Douglas, S. Hodgson, C. Brewer, P.J. Morrison, M. Porteous, P. Peterlongo, S. Manoukian, B. Peissel, D. Zaffaroni, G. Roversi, M. Barile, A. Viel, B. Pasini, L. Ottini, A.L. Putignano, A. Savarese, L. Bernard, P. Radice, S. Healey, A. Spurdle, X. Chen, J. Beesley, M.A. Rookus, S. Verhoef, M.A. Tilanus-Linthorst, M.P. Vreeswijk, C.J. van Asperen, D. Bodmer, M.G.E.M. Ausems, T.A. van Os, M.J. Blok, H.E.J. Meijers-Heijboer, F.B.L. Hogervorst, D.E. Goldgar, S. Buys, E.M. John, A. Miron, M. Southey, M.B. Daly, K. Harbst, A. Borg, J. Rantala, G. Barbany-Bustinza, H. Ehrencrona, M. Stenmark-Askmalm, B. Kaufman, Y. Laitman, R. Milgrom, E. Friedman, S.M. Domchek, K.L. Nathanson, T.R. Rebbeck, O.T. Johannsson, F.J. Couch, X. Wang, Z. Fredericksen, D. Cuadras, V. Moreno, F.K. Pientka, R. Depping, T. Caldes, A. Osorio, J. Benitez, J. Bueren, T. Heikkinen, H. Nevanlinna, U. Hamann, D. Torres, M.A. Caligo, A.K. Godwin, E.N. Imyanitov, R. Janavicius, O.M. Sinilnikova, D. Stoppa-Lyonnet, S. Mazoyer, C. Verny-Pierre, L. Castera, A. de Pauw, Y.J. Bignon, N. Uhrhammer, J.P. Peyrat, P. Vennin, S.F. Ferrer, M.A. Collonge-Rame, I. Mortemousque, L. McGuffog, G. Chenevix-Trench, O.M. Pereira-Smith, A.C. Antoniou, J. Ceron, K. Tominaga, J. Surralles, M.A. Pujana, Christopher M. Maxwell, Julia Kühl, T. Oskar

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18 Citations (Scopus)

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 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
Pages (from-to)R40
Number of pages14
JournalBreast Cancer Research
Volume13
Issue number2
DOIs
Publication statusPublished - 2011

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