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Exploring the link between MORF4L1 and risk of breast cancer

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
Publishing year: 2011
Language: English
Publication/Series: Breast Cancer Research
Volume: 13
Issue: 2
Document type: Journal article
Publisher: BioMed Central

Abstract 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.

Keywords

  • Cancer and Oncology
  • 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

Other

Published
  • ISSN: 1465-5411
Åke Borg
Åke Borg
E-mail: ake.borg [at] med.lu.se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

90

Professor

Oncology and Pathology, MV

MV 404 C21C2

90