TY - JOUR
T1 - FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor
AU - GENESIS
AU - kConFab 25
AU - SWE-BRCA
AU - Peterlongo, Paolo
AU - Catucci, Irene
AU - Colombo, Mara
AU - Caleca, Laura
AU - Mucaki, Eliseos
AU - Bogliolo, Massimo
AU - Marin, Maria
AU - Damiola, Francesca
AU - Bernard, Loris
AU - Pensotti, Valeria
AU - Volorio, Sara
AU - Dall'Olio, Valentina
AU - Meindl, Alfons
AU - Bartram, Claus
AU - Sutter, Christian
AU - Surowy, Harald
AU - Sornin, Valérie
AU - Dondon, Marie Gabrielle
AU - Eon-Marchais, Séverine
AU - Stoppa-Lyonnet, Dominique
AU - Andrieu, Nadine
AU - Sinilnikova, Olga M.
AU - Mitchell, Gillian
AU - James, Paul A.
AU - Thompson, Ella
AU - Marchetti, Marina
AU - Verzeroli, Cristina
AU - Tartari, Carmen
AU - Capone, Gabriele Lorenzo
AU - Putignano, Anna Laura
AU - Genuardi, Maurizio
AU - Medici, Veronica
AU - Marchi, Isabella
AU - Federico, Massimo
AU - Tognazzo, Silvia
AU - Matricardi, Laura
AU - Agata, Simona
AU - Dolcetti, Riccardo
AU - Puppa, Lara Della
AU - Cini, Giulia
AU - Gismondi, Viviana
AU - Viassolo, Valeria
AU - Perfumo, Chiara
AU - Mencarelli, Maria Antonietta
AU - Baldassarri, Margherita
AU - Peissel, Bernard
AU - Roversi, Gaia
AU - Silvestri, Valentina
AU - Rizzolo, Piera
AU - Couch, Fergus J.
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2015/4/9
Y1 - 2015/4/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938903924&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938903924&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddv251
DO - 10.1093/hmg/ddv251
M3 - Article
C2 - 26130695
AN - SCOPUS:84938903924
SN - 0964-6906
VL - 24
SP - 5345
EP - 5355
JO - Human molecular genetics
JF - Human molecular genetics
IS - 18
ER -