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

   

Authors:	Peterlongo, P.; Catucci, I.; Colombo, M.; Caleca, L.; Mucaki, E.; Bogliolo, M.; Marin, M.; Damiola, F.; Bernard, L.; Pensotti, V.; Volorio, S.; Dall'Olio, V.; Meindl, A.; Bartram, C.; Sutter, C.; Surowy, H.; Sornin, V.; Dondon, M. G.; Eon-Marchais, S.; Stoppa-Lyonnet, D.; Andrieu, N.; Sinilnikova, O. M.; Mitchell, G.; James, P. A.; Thompson, E.; Marchetti, M.; Verzeroli, C.; Tartari, C.; Capone, G. L.; Putignano, A. L.; Genuardi, M.; Medici, V.; Marchi, I.; Federico, M.; Tognazzo, S.; Matricardi, L.; Agata, S.; Dolcetti, R.; Della Puppa, L.; Cini, G.; Gismondi, V.; Viassolo, V.; Perfumo, C.; Mencarelli, M. A.; Baldassarri, M.; Peissel, B.; Roversi, G.; Silvestri, V.; Rizzolo, P.; Spina, F.; Vivanet, C.; Tibiletti, M. G.; Caligo, M. A.; Gambino, G.; Tommasi, S.; Pilato, B.; Tondini, C.; Corna, C.; Bonanni, B.; Barile, M.; Osorio, A.; Benítez, J.; Balestrino, L.; Ottini, L.; Manoukian, S.; Pierotti, M. A.; Renieri, A.; Varesco, L.; Couch, F. J.; Wang, X. S.; Devilee, P.; Hilbers, F. S.; van Asperen, C. J.; Viel, A.; Montagna, M.; Cortesi, L.; Diez, O.; Balmana, J.; Hauke, J.; Schmutzler, R. K.; Papi, L.; Pujana, M. A.; Lazaro, C.; Falanga, A.; Offit, K.; Vijai, J.; Campbell, I.; Burwinkel, B.; Kvist, A.; Ehrencrona, H.; Mazoyer, S.; Pizzamiglio, S.; Verderio, P.; Surralles, J.; Rogan, P. K.; Radice, P.
Article Title:	FANCM c.5791C > T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor
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.
Keywords:	proteins; anemia; alleles; disease; palb2; susceptibility gene; rare; cross-links; complementation group-m; xrcc2
Journal Title:	Human Molecular Genetics
Volume:	24
Issue:	18
ISSN:	0964-6906
Publisher:	Oxford University Press
Date Published:	2015-09-15
Start Page:	5345
End Page:	5355
Language:	English
ACCESSION:	WOS:000361317200023
DOI:	10.1093/hmg/ddv251
PROVIDER:	wos
PMCID:	PMC4550823
PUBMED:	26130695
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/82487