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Breast Cancer Research
Published in: Breast Cancer Research 2/2011

Open Access 01-04-2011 | Research article

Exploring the link between MORF4L1 and risk of breast cancer

Authors: Griselda Martrat, Christopher A Maxwell, Emiko Tominaga, Montserrat Porta-de-la-Riva, Núria Bonifaci, Laia Gómez-Baldó, Massimo Bogliolo, Conxi Lázaro, Ignacio Blanco, Joan Brunet, Helena Aguilar, Juana Fernández-Rodríguez, Sheila Seal, Anthony Renwick, Nazneen Rahman, Julia Kühl, Kornelia Neveling, Detlev Schindler, María J Ramírez, María Castellà, Gonzalo Hernández, 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 GEM Ausems, Theo A van Os, Marinus J Blok, Hanne EJ Meijers-Heijboer, Frans BL 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, Víctor Moreno, Friederike K Pientka, Reinhard Depping, Trinidad Caldés, Ana Osorio, Javier Benítez, 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-Agnès Collonge-Rame, Isabelle Mortemousque, Lesley McGuffog, Georgia Chenevix-Trench, Olivia M Pereira-Smith, Antonis C Antoniou, Julián Cerón, Kaoru Tominaga, Jordi Surrallés, Miguel Angel Pujana, EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators

Published in: Breast Cancer Research | Issue 2/2011

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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 γ-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.
Appendix
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Metadata
Title
Exploring the link between MORF4L1 and risk of breast cancer
Authors
Griselda Martrat
Christopher A Maxwell
Emiko Tominaga
Montserrat Porta-de-la-Riva
Núria Bonifaci
Laia Gómez-Baldó
Massimo Bogliolo
Conxi Lázaro
Ignacio Blanco
Joan Brunet
Helena Aguilar
Juana Fernández-Rodríguez
Sheila Seal
Anthony Renwick
Nazneen Rahman
Julia Kühl
Kornelia Neveling
Detlev Schindler
María J Ramírez
María Castellà
Gonzalo Hernández
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 GEM Ausems
Theo A van Os
Marinus J Blok
Hanne EJ Meijers-Heijboer
Frans BL 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
Víctor Moreno
Friederike K Pientka
Reinhard Depping
Trinidad Caldés
Ana Osorio
Javier Benítez
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-Agnès Collonge-Rame
Isabelle Mortemousque
Lesley McGuffog
Georgia Chenevix-Trench
Olivia M Pereira-Smith
Antonis C Antoniou
Julián Cerón
Kaoru Tominaga
Jordi Surrallés
Miguel Angel Pujana
EMBRACE
kConFab
HEBON
BCFR
SWE-BRCA
GEMO Study Collaborators
Publication date
01-04-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2862

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