Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Catucci, Irene, Colombo, Mara ORCID: 0000-0001-5465-354X, Caleca, Laura ORCID: 0000-0002-3381-7493, Mucaki, Eliseos, Bogliolo, Massimo ORCID: 0000-0001-8240-7784, Marin, Maria, Damiola, Francesca ORCID: 0000-0002-0238-1252, Bernard, Loris, Pensotti, Valeria, Volorio, Sara, Dall'Olio, Valentina, Meindl, Alfons, Bartram, Claus, Sutter, Christian, Surowy, Harald ORCID: 0000-0002-3595-9188, Sornin, Valerie, Dondon, Marie-Gabrielle ORCID: 0000-0001-6016-8524, Eon-Marchais, Severine, Stoppa-Lyonnet, Dominique, Andrieu, Nadine, Sinilnikova, Olga M., Mitchell, Gillian, James, Paul A., Thompson, Ella, Marchetti, Marina ORCID: 0000-0001-9036-960X, Verzeroli, Cristina, Tartari, Carmen, Capone, Gabriele Lorenzo, Putignano, Anna Laura, Genuardi, Maurizio ORCID: 0000-0002-7410-8351, Medici, Veronica, Marchi, Isabella, Federico, Massimo ORCID: 0000-0002-5074-3262, Tognazzo, Silvia ORCID: 0000-0002-6260-1261, Matricardi, Laura ORCID: 0000-0002-0241-1810, Agata, Simona, Dolcetti, Riccardo ORCID: 0000-0003-1625-9853, Della Puppa, Lara, Cini, Giulia ORCID: 0000-0002-8696-8922, Gismondi, Viviana, Viassolo, Valeria, Perfumo, Chiara, Mencarelli, Maria Antonietta, Baldassarri, Margherita, Peissel, Bernard ORCID: 0000-0001-9233-3571, Roversi, Gaia, Silvestri, Valentina ORCID: 0000-0003-0712-9379, Rizzolo, Piera ORCID: 0000-0002-3421-1485, Spina, Francesca, Vivanet, Caterina, Tibiletti, Maria Grazia, Caligo, Maria Adelaide, Gambino, Gaetana ORCID: 0000-0002-0671-0244, Tommasi, Stefania ORCID: 0000-0002-2157-2978, Pilato, Brunella, Tondini, Carlo, Corna, Chiara, Bonanni, Bernardo, Barile, Monica, Osorio, Ana ORCID: 0000-0001-8124-3984, Benitez, Javier, Balestrino, Luisa, Ottini, Laura, Manoukian, Siranoush, Pierotti, Marco A., Renieri, Alessandra ORCID: 0000-0002-0846-9220, Varesco, Liliana ORCID: 0000-0003-4871-6668, Couch, Fergus J., Wang, Xianshu, Devilee, Peter ORCID: 0000-0002-8023-2009, Hilbers, Florentine S., van Asperen, Christi J., Viel, Alessandra ORCID: 0000-0003-2804-0840, Montagna, Marco, Cortesi, Laura ORCID: 0000-0001-8950-8561, Diez, Orland, Balmana, Judith ORCID: 0000-0002-0762-6415, Hauke, Jan, Schmutzler, Rita K., Papi, Laura ORCID: 0000-0003-4552-9517, Angel Pujana, Miguel, Lazaro, Conxi, Falanga, Anna ORCID: 0000-0002-5007-3457, Offit, Kenneth, Vijai, Joseph, Campbell, Ian ORCID: 0000-0002-7773-4155, Burwinkel, Barbara, Kvist, Anders ORCID: 0000-0002-1358-0695, Ehrencrona, Hans ORCID: 0000-0002-5589-3622, Mazoyer, Sylvie ORCID: 0000-0002-2135-0160, Pizzamiglio, Sara ORCID: 0000-0002-7759-0550, Verderio, Paolo ORCID: 0000-0002-9231-1281, Surralles, Jordi ORCID: 0000-0002-4041-7519, Rogan, Peter K. and Radice, Paolo ORCID: 0000-0001-6298-4111 (2015). FANCM c.5791C > T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor. Hum. Mol. Genet., 24 (18). S. 5345 - 5356. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Catucci, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colombo, MaraUNSPECIFIEDorcid.org/0000-0001-5465-354XUNSPECIFIED
Caleca, LauraUNSPECIFIEDorcid.org/0000-0002-3381-7493UNSPECIFIED
Mucaki, EliseosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogliolo, MassimoUNSPECIFIEDorcid.org/0000-0001-8240-7784UNSPECIFIED
Marin, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damiola, FrancescaUNSPECIFIEDorcid.org/0000-0002-0238-1252UNSPECIFIED
Bernard, LorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pensotti, ValeriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volorio, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dall'Olio, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartram, ClausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surowy, HaraldUNSPECIFIEDorcid.org/0000-0002-3595-9188UNSPECIFIED
Sornin, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dondon, Marie-GabrielleUNSPECIFIEDorcid.org/0000-0001-6016-8524UNSPECIFIED
Eon-Marchais, SeverineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoppa-Lyonnet, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrieu, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinilnikova, Olga M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, GillianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
James, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thompson, EllaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marchetti, MarinaUNSPECIFIEDorcid.org/0000-0001-9036-960XUNSPECIFIED
Verzeroli, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tartari, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capone, Gabriele LorenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Putignano, Anna LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Genuardi, MaurizioUNSPECIFIEDorcid.org/0000-0002-7410-8351UNSPECIFIED
Medici, VeronicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marchi, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Federico, MassimoUNSPECIFIEDorcid.org/0000-0002-5074-3262UNSPECIFIED
Tognazzo, SilviaUNSPECIFIEDorcid.org/0000-0002-6260-1261UNSPECIFIED
Matricardi, LauraUNSPECIFIEDorcid.org/0000-0002-0241-1810UNSPECIFIED
Agata, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolcetti, RiccardoUNSPECIFIEDorcid.org/0000-0003-1625-9853UNSPECIFIED
Della Puppa, LaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cini, GiuliaUNSPECIFIEDorcid.org/0000-0002-8696-8922UNSPECIFIED
Gismondi, VivianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viassolo, ValeriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perfumo, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mencarelli, Maria AntoniettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldassarri, MargheritaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peissel, BernardUNSPECIFIEDorcid.org/0000-0001-9233-3571UNSPECIFIED
Roversi, GaiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silvestri, ValentinaUNSPECIFIEDorcid.org/0000-0003-0712-9379UNSPECIFIED
Rizzolo, PieraUNSPECIFIEDorcid.org/0000-0002-3421-1485UNSPECIFIED
Spina, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vivanet, CaterinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tibiletti, Maria GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caligo, Maria AdelaideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gambino, GaetanaUNSPECIFIEDorcid.org/0000-0002-0671-0244UNSPECIFIED
Tommasi, StefaniaUNSPECIFIEDorcid.org/0000-0002-2157-2978UNSPECIFIED
Pilato, BrunellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tondini, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corna, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonanni, BernardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barile, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osorio, AnaUNSPECIFIEDorcid.org/0000-0001-8124-3984UNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balestrino, LuisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ottini, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pierotti, Marco A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renieri, AlessandraUNSPECIFIEDorcid.org/0000-0002-0846-9220UNSPECIFIED
Varesco, LilianaUNSPECIFIEDorcid.org/0000-0003-4871-6668UNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XianshuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDorcid.org/0000-0002-8023-2009UNSPECIFIED
Hilbers, Florentine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Asperen, Christi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viel, AlessandraUNSPECIFIEDorcid.org/0000-0003-2804-0840UNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cortesi, LauraUNSPECIFIEDorcid.org/0000-0001-8950-8561UNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balmana, JudithUNSPECIFIEDorcid.org/0000-0002-0762-6415UNSPECIFIED
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papi, LauraUNSPECIFIEDorcid.org/0000-0003-4552-9517UNSPECIFIED
Angel Pujana, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falanga, AnnaUNSPECIFIEDorcid.org/0000-0002-5007-3457UNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vijai, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, IanUNSPECIFIEDorcid.org/0000-0002-7773-4155UNSPECIFIED
Burwinkel, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kvist, AndersUNSPECIFIEDorcid.org/0000-0002-1358-0695UNSPECIFIED
Ehrencrona, HansUNSPECIFIEDorcid.org/0000-0002-5589-3622UNSPECIFIED
Mazoyer, SylvieUNSPECIFIEDorcid.org/0000-0002-2135-0160UNSPECIFIED
Pizzamiglio, SaraUNSPECIFIEDorcid.org/0000-0002-7759-0550UNSPECIFIED
Verderio, PaoloUNSPECIFIEDorcid.org/0000-0002-9231-1281UNSPECIFIED
Surralles, JordiUNSPECIFIEDorcid.org/0000-0002-4041-7519UNSPECIFIED
Rogan, Peter K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
URN: urn:nbn:de:hbz:38-392971
DOI: 10.1093/hmg/ddv251
Journal or Publication Title: Hum. Mol. Genet.
Volume: 24
Number: 18
Page Range: S. 5345 - 5356
Date: 2015
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COMPLEMENTATION GROUP-M; SUSCEPTIBILITY GENE; CROSS-LINKS; ANEMIA; DISEASE; RARE; PROTEINS; ALLELES; PALB2; XRCC2Multiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39297

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