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

Paolo Peterlongo, Irene Catucci, Mara Colombo, Laura Caleca, Eliseos Mucaki, Massimo Bogliolo, Maria Marin, Francesca Damiola, Loris Bernard, Valeria Pensotti, Sara Volorio, Valentina Dall'Olio, Alfons Meindl, Claus Bartram, Christian Sutter, Harald Surowy, Valérie Sornin, Marie Gabrielle Dondon, Séverine Eon-Marchais, Dominique Stoppa-LyonnetNadine Andrieu, Olga M. Sinilnikova, Gillian Mitchell, Paul A. James, Ella Thompson, Marina Marchetti, Cristina Verzeroli, Carmen Tartari, Gabriele Lorenzo Capone, Anna Laura Putignano, Maurizio Genuardi, Veronica Medici, Isabella Marchi, Massimo Federico, Silvia Tognazzo, Laura Matricardi, Simona Agata, Riccardo Dolcetti, Lara Della Puppa, Giulia Cini, Viviana Gismondi, Valeria Viassolo, Chiara Perfumo, Maria Antonietta Mencarelli, Margherita Baldassarri, Bernard Peissel, Gaia Roversi, Valentina Silvestri, Piera Rizzolo, Francesca Spina, Caterina Vivanet, Maria Grazia Tibiletti, Maria Adelaide Caligo, Gaetana Gambino, Stefania Tommasi, Brunella Pilato, Carlo Tondini, Chiara Corna, Bernardo Bonanni, Monica Barile, Ana Osorio, Javier Benitez, Luisa Balestrino, Laura Ottini, Siranoush Manoukian, Marco A. Pierotti, Alessandra Renieri, Liliana Varesco, Fergus J. Couch, Xianshu Wang, Peter Devilee, Florentine S. Hilbers, Christi J. van Asperen, Alessandra Viel, Marco Montagna, Laura Cortesi, Orland Diez, Judith Balmaña, Jan Hauke, Rita K. Schmutzler, Laura Papi, Miguel Angel Pujana, Conxi Lázaro, Anna Falanga, Kenneth Offit, Joseph Vijai, Ian Campbell, Barbara Burwinkel, Anders Kvist, Hans Ehrencrona, Sylvie Mazoyer, Sara Pizzamiglio, Paolo Verderio, Jordi Surralles, Peter K. Rogan, Paolo Radice

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberddv251
Pages (from-to)5345-5355
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number18
DOIs
Publication statusPublished - Apr 9 2015

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Nonsense Codon
DNA Repair
Exons
Odds Ratio
Breast Neoplasms
Confidence Intervals
Mutation
Information Theory
Frameshift Mutation
RNA Precursors
Meta-Analysis
Binding Sites
Familial Breast Cancer
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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; Pensotti, Valeria; Volorio, Sara; Dall'Olio, Valentina; Meindl, Alfons; Bartram, Claus; Sutter, Christian; Surowy, Harald; Sornin, Valérie; Dondon, Marie Gabrielle; Eon-Marchais, Séverine; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M.; Mitchell, Gillian; James, Paul A.; Thompson, Ella; Marchetti, Marina; Verzeroli, Cristina; Tartari, Carmen; Capone, Gabriele Lorenzo; Putignano, Anna Laura; Genuardi, Maurizio; Medici, Veronica; Marchi, Isabella; Federico, Massimo; Tognazzo, Silvia; Matricardi, Laura; Agata, Simona; Dolcetti, Riccardo; Puppa, Lara Della; Cini, Giulia; Gismondi, Viviana; Viassolo, Valeria; Perfumo, Chiara; Mencarelli, Maria Antonietta; Baldassarri, Margherita; Peissel, Bernard; Roversi, Gaia; Silvestri, Valentina; Rizzolo, Piera; Spina, Francesca; Vivanet, Caterina; Tibiletti, Maria Grazia; Caligo, Maria Adelaide; Gambino, Gaetana; Tommasi, Stefania; Pilato, Brunella; Tondini, Carlo; Corna, Chiara; Bonanni, Bernardo; Barile, Monica; Osorio, Ana; Benitez, Javier; Balestrino, Luisa; Ottini, Laura; Manoukian, Siranoush; Pierotti, Marco A.; Renieri, Alessandra; Varesco, Liliana; Couch, Fergus J.; Wang, Xianshu; Devilee, Peter; Hilbers, Florentine S.; van Asperen, Christi J.; Viel, Alessandra; Montagna, Marco; Cortesi, Laura; Diez, Orland; Balmaña, Judith; Hauke, Jan; Schmutzler, Rita K.; Papi, Laura; Pujana, Miguel Angel; Lázaro, Conxi; Falanga, Anna; Offit, Kenneth; Vijai, Joseph; Campbell, Ian; Burwinkel, Barbara; Kvist, Anders; Ehrencrona, Hans; Mazoyer, Sylvie; Pizzamiglio, Sara; Verderio, Paolo; Surralles, Jordi; Rogan, Peter K.; Radice, Paolo.

In: Human Molecular Genetics, Vol. 24, No. 18, ddv251, 09.04.2015, p. 5345-5355.

Research output: Contribution to journalArticle

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, MG, Eon-Marchais, S, Stoppa-Lyonnet, D, Andrieu, N, Sinilnikova, OM, Mitchell, G, James, PA, Thompson, E, Marchetti, M, Verzeroli, C, Tartari, C, Capone, GL, Putignano, AL, Genuardi, M, Medici, V, Marchi, I, Federico, M, Tognazzo, S, Matricardi, L, Agata, S, Dolcetti, R, Puppa, LD, Cini, G, Gismondi, V, Viassolo, V, Perfumo, C, Mencarelli, MA, Baldassarri, M, Peissel, B, Roversi, G, Silvestri, V, Rizzolo, P, Spina, F, Vivanet, C, Tibiletti, MG, Caligo, MA, Gambino, G, Tommasi, S, Pilato, B, Tondini, C, Corna, C, Bonanni, B, Barile, M, Osorio, A, Benitez, J, Balestrino, L, Ottini, L, Manoukian, S, Pierotti, MA, Renieri, A, Varesco, L, Couch, FJ, Wang, X, Devilee, P, Hilbers, FS, van Asperen, CJ, Viel, A, Montagna, M, Cortesi, L, Diez, O, Balmaña, J, Hauke, J, Schmutzler, RK, Papi, L, Pujana, MA, Lázaro, C, Falanga, A, Offit, K, Vijai, J, Campbell, I, Burwinkel, B, Kvist, A, Ehrencrona, H, Mazoyer, S, Pizzamiglio, S, Verderio, P, Surralles, J, Rogan, PK & Radice, P 2015, 'FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor', Human Molecular Genetics, vol. 24, no. 18, ddv251, pp. 5345-5355. https://doi.org/10.1093/hmg/ddv251
Peterlongo, Paolo ; Catucci, Irene ; Colombo, Mara ; Caleca, Laura ; Mucaki, Eliseos ; Bogliolo, Massimo ; Marin, Maria ; Damiola, Francesca ; Bernard, Loris ; Pensotti, Valeria ; Volorio, Sara ; Dall'Olio, Valentina ; Meindl, Alfons ; Bartram, Claus ; Sutter, Christian ; Surowy, Harald ; Sornin, Valérie ; Dondon, Marie Gabrielle ; Eon-Marchais, Séverine ; Stoppa-Lyonnet, Dominique ; Andrieu, Nadine ; Sinilnikova, Olga M. ; Mitchell, Gillian ; James, Paul A. ; Thompson, Ella ; Marchetti, Marina ; Verzeroli, Cristina ; Tartari, Carmen ; Capone, Gabriele Lorenzo ; Putignano, Anna Laura ; Genuardi, Maurizio ; Medici, Veronica ; Marchi, Isabella ; Federico, Massimo ; Tognazzo, Silvia ; Matricardi, Laura ; Agata, Simona ; Dolcetti, Riccardo ; Puppa, Lara Della ; Cini, Giulia ; Gismondi, Viviana ; Viassolo, Valeria ; Perfumo, Chiara ; Mencarelli, Maria Antonietta ; Baldassarri, Margherita ; Peissel, Bernard ; Roversi, Gaia ; Silvestri, Valentina ; Rizzolo, Piera ; Spina, Francesca ; Vivanet, Caterina ; Tibiletti, Maria Grazia ; Caligo, Maria Adelaide ; Gambino, Gaetana ; Tommasi, Stefania ; Pilato, Brunella ; Tondini, Carlo ; Corna, Chiara ; Bonanni, Bernardo ; Barile, Monica ; Osorio, Ana ; Benitez, Javier ; Balestrino, Luisa ; Ottini, Laura ; Manoukian, Siranoush ; Pierotti, Marco A. ; Renieri, Alessandra ; Varesco, Liliana ; Couch, Fergus J. ; Wang, Xianshu ; Devilee, Peter ; Hilbers, Florentine S. ; van Asperen, Christi J. ; Viel, Alessandra ; Montagna, Marco ; Cortesi, Laura ; Diez, Orland ; Balmaña, Judith ; Hauke, Jan ; Schmutzler, Rita K. ; Papi, Laura ; Pujana, Miguel Angel ; Lázaro, Conxi ; Falanga, Anna ; Offit, Kenneth ; Vijai, Joseph ; Campbell, Ian ; Burwinkel, Barbara ; Kvist, Anders ; Ehrencrona, Hans ; Mazoyer, Sylvie ; Pizzamiglio, Sara ; Verderio, Paolo ; Surralles, Jordi ; Rogan, Peter K. ; Radice, Paolo. / FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 18. pp. 5345-5355.
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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.",
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doi = "10.1093/hmg/ddv251",
language = "English",
volume = "24",
pages = "5345--5355",
journal = "Human Molecular Genetics",
issn = "0964-6906",
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T1 - FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor

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 - Spina, Francesca

AU - Vivanet, Caterina

AU - Tibiletti, Maria Grazia

AU - Caligo, Maria Adelaide

AU - Gambino, Gaetana

AU - Tommasi, Stefania

AU - Pilato, Brunella

AU - Tondini, Carlo

AU - Corna, Chiara

AU - Bonanni, Bernardo

AU - Barile, Monica

AU - Osorio, Ana

AU - Benitez, Javier

AU - Balestrino, Luisa

AU - Ottini, Laura

AU - Manoukian, Siranoush

AU - Pierotti, Marco A.

AU - Renieri, Alessandra

AU - Varesco, Liliana

AU - Couch, Fergus J.

AU - Wang, Xianshu

AU - Devilee, Peter

AU - Hilbers, Florentine S.

AU - van Asperen, Christi J.

AU - Viel, Alessandra

AU - Montagna, Marco

AU - Cortesi, Laura

AU - Diez, Orland

AU - Balmaña, Judith

AU - Hauke, Jan

AU - Schmutzler, Rita K.

AU - Papi, Laura

AU - Pujana, Miguel Angel

AU - Lázaro, Conxi

AU - Falanga, Anna

AU - Offit, Kenneth

AU - Vijai, Joseph

AU - Campbell, Ian

AU - Burwinkel, Barbara

AU - Kvist, Anders

AU - Ehrencrona, Hans

AU - Mazoyer, Sylvie

AU - Pizzamiglio, Sara

AU - Verderio, Paolo

AU - Surralles, Jordi

AU - Rogan, Peter K.

AU - Radice, Paolo

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.

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