Exploring the link between MORF4L1 and risk of breast cancer
Authors: Martrat Griselda , Maxwell Christopher A , Tominaga Emiko , Porta-de-la-Riva Montserrat , Bonifaci Núria , Gómez-Baldó Laia , Bogliolo Massimo , Lázaro Conxi , Blanco Ignacio , Brunet Joan , Aguilar Helena , Fernández-Rodríguez Juana , Seal Sheila , Renwick Anthony , Rahman Nazneen , Kühl Julia , Neveling Kornelia , Schindler Detlev , Ramírez María J , Castellà María , Hernández Gonzalo ,   EMBRACE, 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 ,   kConFab, Rookus Matti A , Verhoef Senno , Tilanus-Linthorst Madeleine A , Vreeswijk Maaike P , Asperen Christi J , Bodmer Danielle , Ausems Margreet GEM , van Os Theo A , Blok Marinus J , Meijers-Heijboer Hanne EJ , Hogervorst Frans BL ,   HEBON, Goldgar David E , Buys Saundra , John Esther M , Miron Alexander , Southey Melissa , Daly Mary B ,   BCFR,   SWE-BRCA, Harbst Katja , Borg Åke , 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 Víctor , Pientka Friederike K , Depping Reinhard , Caldés Trinidad , Osorio Ana , Benítez Javier , Bueren Juan , Heikkinen Tuomas , Nevanlinna Heli , Hamann Ute , Torres Diana , Caligo Maria Adelaide , Godwin Andrew K , Imyanitov Evgeny N , Janavicius Ramunas ,   GEMO Study Collaborators, 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-Agnès , Mortemousque Isabelle , McGuffog Lesley , Chenevix-Trench Georgia , Pereira-Smith Olivia M , Antoniou Antonis C , Cerón Julián , Tominaga Kaoru , Surrallés Jordi , Pujana Miguel Angel 
Published: June 2011

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 andCaenorhabditis elegansmodels 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 forBRCA1/2mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573BRCA1/2mutation carriers for associations with BrCa risk.

Results

A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1gene). Results in human, mouse andC. elegansmodels 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 BRCA2C. elegansorthologs 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/MORF4L1in unclassified FA patients and BrCa familial cases. Finally, no significant associations between commonMORF4L1variants and BrCa risk forBRCA1orBRCA2mutation 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 atMORF4L1and BrCa risk amongBRCA2mutation carriers.