| Literature DB >> 26130695 |
Paolo Peterlongo1, Irene Catucci2, Mara Colombo3, Laura Caleca3, Eliseos Mucaki4, Massimo Bogliolo5, Maria Marin5, Francesca Damiola6, Loris Bernard7, Valeria Pensotti8, Sara Volorio8, Valentina Dall'Olio8, Alfons Meindl9, Claus Bartram10, Christian Sutter10, Harald Surowy11, Valérie Sornin6, Marie-Gabrielle Dondon12, Séverine Eon-Marchais12, Dominique Stoppa-Lyonnet13, Nadine Andrieu12, Olga M Sinilnikova14, Gillian Mitchell15, Paul A James15, Ella Thompson16, Marina Marchetti17, Cristina Verzeroli18, Carmen Tartari17, Gabriele Lorenzo Capone19, Anna Laura Putignano19, Maurizio Genuardi20, Veronica Medici21, Isabella Marchi21, Massimo Federico21, Silvia Tognazzo22, Laura Matricardi22, Simona Agata22, Riccardo Dolcetti23, Lara Della Puppa24, Giulia Cini24, Viviana Gismondi25, Valeria Viassolo25, Chiara Perfumo25, Maria Antonietta Mencarelli26, Margherita Baldassarri26, Bernard Peissel27, Gaia Roversi27, Valentina Silvestri28, Piera Rizzolo28, Francesca Spina29, Caterina Vivanet29, Maria Grazia Tibiletti30, Maria Adelaide Caligo31, Gaetana Gambino31, Stefania Tommasi32, Brunella Pilato32, Carlo Tondini33, Chiara Corna33, Bernardo Bonanni34, Monica Barile34, Ana Osorio35, Javier Benitez35, Luisa Balestrino29, Laura Ottini28, Siranoush Manoukian27, Marco A Pierotti36, Alessandra Renieri26, Liliana Varesco25, Fergus J Couch37, Xianshu Wang37, Peter Devilee38, Florentine S Hilbers39, Christi J van Asperen40, Alessandra Viel24, Marco Montagna22, Laura Cortesi21, Orland Diez41, Judith Balmaña42, Jan Hauke43, Rita K Schmutzler43, Laura Papi44, Miguel Angel Pujana45, Conxi Lázaro45, Anna Falanga17, Kenneth Offit46, Joseph Vijai46, Ian Campbell47, Barbara Burwinkel11, Anders Kvist48, Hans Ehrencrona49, Sylvie Mazoyer6, Sara Pizzamiglio50, Paolo Verderio50, Jordi Surralles5, Peter K Rogan4, Paolo Radice2.
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.Entities:
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Year: 2015 PMID： 26130695 PMCID： PMC4550823 DOI： 10.1093/hmg/ddv251
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150