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

Peterlongo, Paolo; Catucci, Irene; Colombo, Mara; Caleca, Laura; Mucaki, Eliseos; Bogliolo, Massimo; Marin, Maria; Damiola, Francesca; Bernard, Loris and Pensotti, Valeria, et al. (2015) In Human Molecular Genetics 24(18). p.5345-5355
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... (More)
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. (Less)
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Human Molecular Genetics
volume
24
issue
18
pages
5345 - 5355
publisher
Oxford University Press
external identifiers
  • pmid:26130695
  • wos:000361317200023
  • scopus:84938903924
ISSN
0964-6906
DOI
10.1093/hmg/ddv251
language
English
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yes
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e64ee922-cb52-4b54-9cc0-a9fe3ab655a5 (old id 7751268)
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http://www.ncbi.nlm.nih.gov/pubmed/26130695?dopt=Abstract
date added to LUP
2015-08-01 21:22:35
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2017-11-12 03:16:46
@article{e64ee922-cb52-4b54-9cc0-a9fe3ab655a5,
  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.},
  author       = {Peterlongo, Paolo and Catucci, Irene and Colombo, Mara and Caleca, Laura and Mucaki, Eliseos and Bogliolo, Massimo and Marin, Maria and Damiola, Francesca and Bernard, Loris and Pensotti, Valeria and Volorio, Sara and Dall'Olio, Valentina and Meindl, Alfons and Bartram, Claus and Sutter, Christian and Surowy, Harald and Sornin, Valérie and Dondon, Marie-Gabrielle and Eon-Marchais, Séverine and Stoppa-Lyonnet, Dominique and Andrieu, Nadine and Sinilnikova, Olga M and Mitchell, Gillian and James, Paul A and Thompson, Ella and Marchetti, Marina and Verzeroli, Cristina and Tartari, Carmen and Capone, Gabriele Lorenzo and Putignano, Anna Laura and Genuardi, Maurizio and Medici, Veronica and Marchi, Isabella and Federico, Massimo and Tognazzo, Silvia and Matricardi, Laura and Agata, Simona and Dolcetti, Riccardo and Puppa, Lara Della and Cini, Giulia and Gismondi, Viviana and Viassolo, Valeria and Perfumo, Chiara and Mencarelli, Maria Antonietta and Baldassarri, Margherita and Peissel, Bernard and Roversi, Gaia and Silvestri, Valentina and Rizzolo, Piera and Spina, Francesca and Vivanet, Caterina and Tibiletti, Maria Grazia and Caligo, Maria Adelaide and Gambino, Gaetana and Tommasi, Stefania and Pilato, Brunella and Tondini, Carlo and Corna, Chiara and Bonanni, Bernardo and Barile, Monica and Osorio, Ana and Benitez, Javier and Balestrino, Luisa and Ottini, Laura and Manoukian, Siranoush and Pierotti, Marco A and Renieri, Alessandra and Varesco, Liliana and Couch, Fergus J and Wang, Xianshu and Devilee, Peter and Hilbers, Florentine S and van Asperen, Christi J and Viel, Alessandra and Montagna, Marco and Cortesi, Laura and Diez, Orland and Balmaña, Judith and Hauke, Jan and Schmutzler, Rita K and Papi, Laura and Pujana, Miguel Angel and Lázaro, Conxi and Falanga, Anna and Offit, Kenneth and Vijai, Joseph and Campbell, Ian and Burwinkel, Barbara and Kvist, Anders and Ehrencrona, Hans and Mazoyer, Sylvie and Pizzamiglio, Sara and Verderio, Paolo and Surralles, Jordi and Rogan, Peter K and Radice, Paolo},
  issn         = {0964-6906},
  language     = {eng},
  number       = {18},
  pages        = {5345--5355},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.},
  url          = {http://dx.doi.org/10.1093/hmg/ddv251},
  volume       = {24},
  year         = {2015},
}