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Hum Mol Genet. 2015 Sep 15;24(18):5345-55. doi: 10.1093/hmg/ddv251. Epub 2015 Jun 30.

FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.

Author information

1
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, paolo.peterlongo@ifom.eu.
2
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine.
3
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine.
4
Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
5
Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona and Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
6
Cancer Research Centre of Lyon, CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1, Centre Léon Bérard, Lyon, France.
7
Department of Experimental Oncology and Cogentech, Cancer Genetic Test Laboratory, Milan, Italy.
8
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy, Cogentech, Cancer Genetic Test Laboratory, Milan, Italy.
9
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
10
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
11
Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany, Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
INSERM, U900, Paris, France, Institut Curie, Paris, France, Mines ParisTech, Fontainebleau, France.
13
Service de Génétique Oncologique, Institut Curie, Paris, France, INSERM, U830, Paris, France, Université Paris-Descartes, Paris, France.
14
Cancer Research Centre of Lyon, CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1, Centre Léon Bérard, Lyon, France, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
15
Familial Cancer Centre, Sir Peter MacCallum Department of Oncology and.
16
Cancer Genetics Laboratory and Sir Peter MacCallum Department of Oncology and.
17
Department of Immunohematology and Transfusion Medicine and.
18
Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
19
Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Firenze, Italy, FiorGen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.
20
Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Firenze, Italy, FiorGen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy, Institute of Medical Genetics, 'A. Gemelli' School of Medicine, Catholic University, Rome, Italy.
21
Dipartimento di Oncologia, Ematologia e Malattie dell'Apparato Respiratorio, Università di Modena e Reggio Emilia, Modena, Italy.
22
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy.
23
Cancer Bio-Immunotherapy Unit and.
24
Unit of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano (PN), Italy.
25
Unit of Hereditary Cancers, IRCCS AOU San Martino - IST, Genoa, Italy.
26
Medical Genetics, University of Siena, Siena, Italy, Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
27
Unit of Medical Genetics, Department of Preventive and Predictive Medicine.
28
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
29
SC Medical Genetics, ASl8 Cagliari, Cagliari, Italy.
30
Unit of Pathology, Ospedale di Circolo, Varese, Italy.
31
Section of Genetic Oncology, University Hospital and University of Pisa, Pisa, Italy.
32
IRCCS Istituto Tumori 'Giovanni Paolo II', Molecular Genetics Laboratory, Bari, Italy.
33
Unit of Medical Oncology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
34
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
35
Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain, Spanish Genotyping Centre (CEGEN), Madrid, Spain.
36
Scientific Directorate and.
37
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
38
Department of Human Genetics, Department of Pathology and.
39
Department of Human Genetics.
40
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
41
Oncogenetics Group, Hospital Universitari de la Vall d'Hebron, Barcelona, Spain, Vall d́Hebron Institute of Oncology (VHIO), Barcelona, Spain, Universitat Autònoma de Barcelona, Barcelona, Spain.
42
Vall d́Hebron Institute of Oncology (VHIO), Barcelona, Spain, Department of Medical Oncology, Hospital Universitari de la Vall d́Hebron, Barcelona, Spain.
43
Center for Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
44
Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Firenze, Italy.
45
Catalan Institute of Oncology - IDIBELL, Barcelona, Spain.
46
Clinical Genetics Service, Department of Medicine and Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
47
Cancer Genetics Laboratory and Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
48
Division of Oncology, Department of Clinical Sciences.
49
Department of Clinical Genetics, Laboratory Medicine, Office for Medical Services and Department of Clinical Genetics, Lund University, Lund, Sweden.
50
Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Abstract

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

PMID:
26130695
PMCID:
PMC4550823
DOI:
10.1093/hmg/ddv251
[Indexed for MEDLINE]
Free PMC Article

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