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Open Access Highly Accessed Research article

Exploring the link between MORF4L1 and risk of breast cancer

Griselda Martrat12, Christopher A Maxwell12, Emiko Tominaga3, Montserrat Porta-de-la-Riva4, Núria Bonifaci25, Laia Gómez-Baldó12, Massimo Bogliolo67, Conxi Lázaro8, Ignacio Blanco8, Joan Brunet9, Helena Aguilar1, Juana Fernández-Rodríguez8, Sheila Seal10, Anthony Renwick10, Nazneen Rahman10, Julia Kühl11, Kornelia Neveling11, Detlev Schindler11, María J Ramírez67, María Castellà67, Gonzalo Hernández67, EMBRACE12, Douglas F Easton12, Susan Peock12, Margaret Cook12, Clare T Oliver12, Debra Frost12, Radka Platte13, D Gareth Evans14, Fiona Lalloo14, Rosalind Eeles15, Louise Izatt16, Carol Chu17, Rosemarie Davidson18, Kai-Ren Ong19, Jackie Cook20, Fiona Douglas21, Shirley Hodgson22, Carole Brewer23, Patrick J Morrison24, Mary Porteous25, Paolo Peterlongo2627, Siranoush Manoukian28, Bernard Peissel28, Daniela Zaffaroni28, Gaia Roversi28, Monica Barile29, Alessandra Viel30, Barbara Pasini31, Laura Ottini32, Anna Laura Putignano3334, Antonella Savarese35, Loris Bernard36, Paolo Radice2627, Sue Healey37, Amanda Spurdle37, Xiaoqing Chen37, Jonathan Beesley37, kConFab38, Matti A Rookus39, Senno Verhoef40, Madeleine A Tilanus-Linthorst41, Maaike P Vreeswijk42, Christi J Asperen42, Danielle Bodmer43, Margreet GEM Ausems44, Theo A van Os45, Marinus J Blok46, Hanne EJ Meijers-Heijboer47, Frans BL Hogervorst40, HEBON48, David E Goldgar49, Saundra Buys50, Esther M John51, Alexander Miron52, Melissa Southey53, Mary B Daly54, BCFR55, SWE-BRCA56, Katja Harbst57, Åke Borg57, Johanna Rantala58, Gisela Barbany-Bustinza58, Hans Ehrencrona59, Marie Stenmark-Askmalm60, Bella Kaufman61, Yael Laitman62, Roni Milgrom62, Eitan Friedman6263, Susan M Domchek64, Katherine L Nathanson65, Timothy R Rebbeck66, Oskar Thor Johannsson6768, Fergus J Couch6970, Xianshu Wang69, Zachary Fredericksen70, Daniel Cuadras71, Víctor Moreno25, Friederike K Pientka72, Reinhard Depping72, Trinidad Caldés73, Ana Osorio74, Javier Benítez74, Juan Bueren75, Tuomas Heikkinen76, Heli Nevanlinna76, Ute Hamann77, Diana Torres78, Maria Adelaide Caligo79, Andrew K Godwin80, Evgeny N Imyanitov81, Ramunas Janavicius82, GEMO Study Collaborators83, Olga M Sinilnikova8485, Dominique Stoppa-Lyonnet868788, Sylvie Mazoyer85, Carole Verny-Pierre85, Laurent Castera86, Antoine de Pauw86, Yves-Jean Bignon89, Nancy Uhrhammer89, Jean-Philippe Peyrat90, Philippe Vennin91, Sandra Fert Ferrer92, Marie-Agnès Collonge-Rame93, Isabelle Mortemousque94, Lesley McGuffog12, Georgia Chenevix-Trench37, Olivia M Pereira-Smith3, Antonis C Antoniou12, Julián Cerón4*, Kaoru Tominaga3*, Jordi Surrallés67* and Miguel Angel Pujana125*

Author Affiliations

1 Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran Via 199, L'Hospitalet del Llobregat 08908, Spain

2 Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, IDIBELL, Gran Via 199, L'Hospitalet del Llobregat 08908, Spain

3 Sam and Ann Barshop Institute for Longevity and Aging Studies, Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA

4 Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, IDIBELL, Gran Via 199, L'Hospitalet del Llobregat 08908, Spain

5 Biomarkers and Susceptibility Unit, Catalan Institute of Oncology, IDIBELL, Gran Via 199, L'Hospitalet del Llobregat 08908, Spain

6 Department of Genetics and Microbiology, Autonomous University of Barcelona, Campus Bellaterra s/n, Bellaterra 08193, Spain

7 Biomedical Research Centre Network for Rare Diseases (CIBERER), Autonomous University of Barcelona, Campus Bellaterra s/n, Bellaterra 08193, Spain

8 Hereditary Cancer Programme, Catalan Institute of Oncology, IDIBELL, Gran Via 199, L'Hospitalet del Llobregat 08908, Spain

9 Hereditary Cancer Programme, Catalan Institute of Oncology, Hospital Josep Trueta, Girona Biomedical Research Institute (IdIBGi), Avinguda França s/n, Girona 17007, Spain

10 Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK

11 Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, Würzburg D-97074, Germany

12 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK

13 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK

14 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Hathersage Road, Manchester M13 9LW, UK

15 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton SM2 5NG, UK

16 Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Guys Hospital, Great Maze Pond, London SE1 9RT, UK

17 Yorkshire Regional Genetics Service, St James's Hospital, Beckett Street, Leeds LS9 TF7, UK

18 Ferguson-Smith Centre for Clinical Genetics, Block 4 Yorhill NHS Trust, Yorkhill, Glasgow G3 8SJ, UK

19 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Mindelsohn Way, Birmingham B15 2TG, UK

20 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK

21 Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Central Parkway, Newcastle upon Tyne NE1 4EP, UK

22 Clinical Genetics Department, St George's Hospital, University of London, Cranmer Terrace, London SW17 0RE, UK

23 Department of Clinical Genetics, Royal Devon & Exeter Hospital, Gladstone Road, Exeter EX1 2ED, UK

24 Northern Ireland Regional Genetics Centre, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, UK

25 South East of Scotland Regional Genetics Service, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK

26 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, Milan 20133, Italy

27 Department of Preventive and Predictive Medicine, IFOM Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy

28 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS INT, Via Giacomo Venezian 1, Milan 20133, Italy

29 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, Milan 20141, Italy

30 Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), IRCCS, Via Franco Gallini 2, Aviano 33081, Italy

31 Department of Genetics, Biology and Biochemistry, University of Turin, Via Santena 19, Turin 10126, Italy

32 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy

33 Unit of Medical Genetics, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, Florence 50139, Italy

34 Fiorgen Foundation for Pharmacogenomics, Via L Sacconi 6, Sesto Fiorentino 50019, Italy

35 Division of Medical Oncology, Regina Elena Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy

36 Department of Experimental Oncology, IEO, Via Ripamonti 435, Milan 20141, Italy

37 Division of Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Brisbane 4029, Australia

38 The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Center, A'Beckett Street, Melbourne, VIC 8006, Australia

39 Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands

40 Family Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands

41 Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, Rotterdam 3075 AE, The Netherlands

42 Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands

43 DNA Diagnostics, Department of Human Genetics, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6520 GA, The Netherlands

44 Department of Medical Genetics, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands

45 Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands

46 Department of Clinical Genetics, University Hospital Maastricht, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands

47 Department of Clinical Genetics, VU Medical Center, De Boelelaan 1117, Amsterdam 1007 MB, The Netherlands

48 Hereditary Breast and Ovarian Cancer Group, Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands

49 Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132, USA

50 Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112, USA

51 Cancer Prevention Institute of California, 2201 Walnut Avenue, Fremont, CA 94538, USA

52 Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Surgery, Harvard Medical School, 27 Drydock Avenue, Boston, MA 02210, USA

53 Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, 723 Swanston Street, The University of Melbourne, VIC 3010, Australia

54 Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

55 Breast Cancer Family Registry, Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132, USA

56 Swedish Breast Cancer Study, Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Barngatan 2B, Lund S-221 85, Sweden

57 Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Barngatan 2B, Lund S-221 85, Sweden

58 Department of Clinical Genetics, Karolinska University Hospital, L5:03, Stockholm S-171 76, Sweden

59 Departament of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala S-751 85, Sweden

60 Department of Oncology, University Hospital, Hälsouniversitetet Universitetssjukhuset, Linköping S-581 85, Sweden

61 The Institute of Oncology, Chaim Sheba Medical Center, 2 Sheba Road, Ramat Gan 52621, Israel

62 The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, 2 Sheba Road, Ramat Gan 52621, Israel

63 Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

64 Abramson Cancer Center, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA

65 Department of Medicine, Medical Genetics and Abramson Cancer Center, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA

66 Center for Clinical Epidemiology and Biostatistics and Abramson Cancer Center, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA

67 Department of Oncology, 20A Landspitali-LSH v/Hringbraut, Reykjavik 101, Iceland

68 Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, Reykjavik 101, Iceland

69 Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

70 Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

71 Statistical Assessment Service, IDIBELL, Feixa Llarga s/n, L'Hospitalet del Llobregat 08908, Spain

72 Department of Physiology, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, Lübeck D-23538, Germany

73 Medical Oncology Branch, Hospital Clínico San Carlos, Martín Lagos s/n, Madrid 28040, Spain

74 Human Cancer Genetics Programme, Spanish National Cancer Research Centre and CIBERER, Melchor Fernández Almagro 3, Madrid 28029, Spain

75 Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas, Medioambientales, y Tecnológicas (CIEMAT) and CIBERER, Avenida Complutense 22, Madrid 28040, Spain

76 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 8, Helsinki 00290, Finland

77 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, Heidelberg D-69120, Germany

78 Instituto de Genética Humana, Pontificia Universidad Javeriana, Carrera 7 número 40-62, Bogotá, Colombia

79 Section of Genetic Oncology, University Hospital of Pisa, Via Roma 57, Pisa 56127, Italy

80 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA

81 Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, 68 Leningradskaya Street, St Petersburg 197758, Russia

82 Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Santariskiu 2, Vilnius LT-08661, Lithuania

83 Cancer Genetics Network 'Groupe Génétique et Cancer', Fédération Nationale des Centres de Lutte Contre le Cancer, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 Rue Laennec, Lyon 6008, France

84 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 Rue Laennec, Lyon 6008, France

85 INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 Rue Laennec, Lyon 69373, France

86 Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, Paris 75248, France

87 Unité INSERM U830, Institut Curie, 26 rue d'Ulm, Paris 75248, France

88 Faculté de Médecine, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris 75006, France

89 Département d'Oncogénétique, Centre Jean Perrin, Université de Clermont-Ferrand, 58 Rue Montalembert, Clermont-Ferrand 63011, France

90 Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, 3 Rue Frédéric Combemale, Lille 59020, France

91 Consultation d'Oncogénétique, Centre Oscar Lambret, 3 Rue Frédéric Combemale, Lille 59020, France

92 Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, Place Docteur Francois Chiron, Chambéry 73011, France

93 Service de Génétique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, 2 Place St Jacques, Besançon 25000, France

94 Service de Génétique, Centre Hospitalier Universitaire Bretonneau, 2 Boulevard Tonnellé, Tours 37000, France

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Breast Cancer Research 2011, 13:R40  doi:10.1186/bcr2862

Published: 5 April 2011

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.