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Journal Articles Breast Cancer Research Year : 2011

Exploring the link between MORF4L1 and risk of breast cancer.

Griselda Martrat (1, 2) , Christopher Maxwell (1, 2) , Emiko Tominaga (3) , Montserrat Porta-De-La-Riva (4) , Núria Bonifaci (2, 5) , Laia Gómez-Baldó (1, 2) , Massimo Bogliolo (6, 7) , Conxi Lázaro (8) , Ignacio Blanco (8) , Joan Brunet (8) , Helena Aguilar (1) , Juana Fernández-Rodríguez (8) , Sheila Seal (9) , Anthony Renwick (9) , Nazneen Rahman (9) , Julia Kühl (10) , Kornelia Neveling (10) , Detlev Schindler (10) , María Ramírez (6, 7) , María Castellà (6, 7) , Gonzalo Hernández (6, 7) , Douglas Easton (11) , Susan Peock (11) , Margaret Cook (11) , Clare Oliver (11) , Debra Frost (11) , Radka Platte (12) , D Gareth Evans (13) , Fiona Lalloo (13) , Rosalind Eeles (14) , Louise Izatt (15) , Carol Chu (16) , Rosemarie Davidson (17) , Kai-Ren Ong (18) , Jackie Cook (19) , Fiona Douglas (20) , Shirley Hodgson (21) , Carole Brewer (22) , Patrick Morrison (23) , Mary Porteous (24) , Paolo Peterlongo (25, 26) , Siranoush Manoukian (27) , Bernard Peissel (27) , Daniela Zaffaroni (27) , Gaia Roversi (27) , Monica Barile (28) , Alessandra Viel (29) , Barbara Pasini (30) , Laura Ottini (31) , Anna Laura Putignano (32, 33) , Antonella Savarese (34) , Loris Bernard (35) , Paolo Radice (25, 26) , Sue Healey (36) , Amanda Spurdle (36) , Xiaoqing Chen (36) , Jonathan Beesley (36) , Matti Rookus (37) , Senno Verhoef (38) , Madeleine Tilanus-Linthorst (39) , Maaike Vreeswijk (40) , Christi Asperen (40) , Danielle Bodmer (41) , Margreet Ausems (42) , Theo van Os (43) , Marinus Blok (44) , Hanne Meijers-Heijboer (45) , Frans Hogervorst (38) , David E. Goldgar (46) , Saundra Buys (47) , Esther John (48) , Alexander Miron (49, 50) , Melissa Southey (51) , Mary Daly (52) , Katja Harbst (53) , Åke Borg (53) , Johanna Rantala (54) , Gisela Barbany-Bustinza (54) , Hans Ehrencrona (55) , Marie Stenmark-Askmalm (56) , Bella Kaufman (57) , Yael Laitman (58) , Roni Milgrom (58) , Eitan Friedman (58, 59) , Susan Domchek (60) , Katherine Nathanson (61) , Timothy Rebbeck (62) , Oskar Thor Johannsson (63, 64) , Fergus Couch (65, 66) , Xianshu Wang (65) , Zachary Fredericksen (66) , Daniel Cuadras (67) , Víctor Moreno (2, 5) , Friederike Pientka (68) , Reinhard Depping (68) , Trinidad Caldés (69) , Ana Osorio (70) , Javier Benítez (70) , Juan Bueren (71) , Tuomas Heikkinen (72) , Heli Nevanlinna (72) , Ute Hamann (73) , Diana Torres (74) , Maria Adelaide Caligo (75) , Andrew Godwin (76) , Evgeny Imyanitov (77) , Ramunas Janavicius (78) , Olga Sinilnikova (79, 80) , Dominique Stoppa-Lyonnet (81, 82) , Sylvie Mazoyer (80) , Carole Verny-Pierre (80) , Laurent Castera (81) , Antoine de Pauw (81) , Yves-Jean Bignon (83) , Nancy Uhrhammer (83) , Jean-Philippe Peyrat (84) , Philippe Vennin (85) , Sandra Fert Ferrer (86) , Marie-Agnès Collonge-Rame (87) , Isabelle Mortemousque (88) , Lesley Mcguffog (11) , Georgia Chenevix-Trench (36) , Olivia Pereira-Smith (3) , Antonis Antoniou (11) , Julián Cerón (4) , Kaoru Tominaga (3) , Jordi Surrallés (6, 7) , Miguel Angel Pujana (1, 2, 5)
1 Translational Research Laboratory
2 CIBERESP - Biomedical Research Centre Network for Epidemiology and Public Health
3 Department of Cellular and Structural Biology
4 Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment
5 Biomarkers and Susceptibility Unit
6 Department of Genetics and Microbiology
7 CIBERER - Biomedical Research Centre Network for Rare Diseases
8 Genetic Counseling and Hereditary Cancer Programme
9 Section of Cancer Genetics
10 Department of Human Genetics
11 Strangeways Research Laboratory
12 Centre for Cancer Genetic Epidemiology [Cambridge]
13 Genetic Medicine
14 Oncogenetics Team
15 Clinical Genetics Department
16 Yorkshire Regional Genetics Service
17 Ferguson-Smith Centre for Clinical Genetics
18 West Midlands Regional Genetics Service
19 Sheffield Clinical Genetics Service
20 Institute of Human Genetics
21 Clinical Genetics Department
22 Department of Clinical Genetics
23 Northern Ireland Regional Genetics Centre
24 South East of Scotland Regional Genetics Service
25 Unit of Molecular Bases of Genetic Risk and Genetic Testing
26 Department of Preventive and Predictive Medicine
27 Unit of Medical Genetics
28 Division of Cancer Prevention and Genetics
29 CRO - Centro di Riferimento Oncologico
30 Department of Genetics, Biology and Biochemistry
31 Department of Molecular Medicine
32 Unit of Medical Genetics
33 Fiorgen Foundation for Pharmacogenomics
34 Division of Medical Oncology
35 Department of Experimental Oncology
36 Division of Genetics and Population Health
37 Department of Epidemiology
38 Family Cancer Clinic
39 Department of Surgical Oncology
40 Center for Human and Clinical Genetics
41 DNA Diagnostics
42 Department of Medical Genetics
43 Department of Clinical Genetics
44 Department of Clinical Genetics
45 Department of Clinical Genetics
46 Department of Dermatology
47 Department of Internal Medicine
48 Cancer Prevention Institute of California
49 Department of Cancer Biology
50 Department of Surgery
51 MEGA - Centre for Molecular, Environmental, Genetic and Analytic Epidemiology
52 Division of Population Science
53 Department of Oncology, Clinical Sciences
54 Department of Clinical Genetics
55 Department of Genetics and Pathology
56 Department of Oncology
57 The Institute of Oncology
58 The Susanne Levy Gertner Oncogenetics Unit
59 Sackler Faculty of Medicine
60 Abramson Cancer Center
61 Department of Medicine, Medical Genetics
62 Center for Clinical Epidemiology and Biostatistics
63 Department of Oncology
64 Faculty of Medicine
65 Department of Laboratory Medicine and Pathology
66 Department of Health Sciences Research
67 Statistical Assessment Service
68 Department of Physiology
69 Medical Oncology Branch
70 Human Cancer Genetics Programme
71 Division of Hematopoiesis and Gene Therapy
72 Department of Obstetrics and Gynecology
73 Molecular Genetics of Breast Cancer
74 Instituto de Genética Humana
75 Section of Genetic Oncology
76 Department of Pathology and Laboratory Medicine
77 Laboratory of Molecular Oncology
78 Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion
79 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
80 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
81 Service de Génétique Oncologique
82 U830 - Unité de génétique et biologie des cancers
83 Département d'Oncogénétique
84 Laboratoire d'Oncologie Moléculaire Humaine
85 Consultation d'Oncogénétique
86 Laboratoire de Génétique Chromosomique
87 Département de Génétique et Reproduction
88 Service de génétique [Tours]
Helena Aguilar
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Sheila Seal
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Anthony Renwick
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Nazneen Rahman
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Julia Kühl
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Kornelia Neveling
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Louise Izatt
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Carol Chu
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Jackie Cook
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Fiona Douglas
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Patrick Morrison
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Loris Bernard
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Sue Healey
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Amanda Spurdle
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Xiaoqing Chen
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Jonathan Beesley
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Matti Rookus
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Senno Verhoef
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Madeleine Tilanus-Linthorst
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Maaike Vreeswijk
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Christi Asperen
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Danielle Bodmer
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Margreet Ausems
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Theo van Os
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Marinus Blok
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Hanne Meijers-Heijboer
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Frans Hogervorst
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David E. Goldgar
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Marie Stenmark-Askmalm
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Susan Domchek
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Zachary Fredericksen
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Daniel Cuadras
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Reinhard Depping
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Trinidad Caldés
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Abstract

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.

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Cancer
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Dates and versions

inserm-00622815 , version 1 (12-09-2011)

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Griselda Martrat, Christopher Maxwell, Emiko Tominaga, Montserrat Porta-De-La-Riva, Núria Bonifaci, et al.. Exploring the link between MORF4L1 and risk of breast cancer.. Breast Cancer Research, 2011, 13 (2), pp.R40. ⟨10.1186/bcr2862⟩. ⟨inserm-00622815⟩
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