The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gen...
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| Veröffentlicht in: | NPJ BREAST CANCER 2019-11, Vol.5 |
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| creator | Figlioli, Gisella Bogliolo, Massimo Catucci, Irene Caleca, Laura Viz Lasheras, Sandra Pujol, Roser Kiiski, Johanna Muranen, Taru A Barnes, Daniel R Dennis, Joe Michailidou, Kyriaki Bolla, Manjeet K Leslie, Goska Aalfs, Cora M Adank, Muriel A Adlard, Julian Agata, Simona Cadoo, Karen Agnarsson, Bjarni A Ahearn, Thomas Aittomaki, Kristiina Ambrosone, Christine B Andrews, Lesley Anton-Culver, Hoda Antonenkova, Natalia N Arndt, Volker Arnold, Norbert Aronson, Kristan J Arun, Banu K Asseryanis, Ella Auber, Bernd Auvinen, Paivi Azzollini, Jacopo Balmana, Judith Barkardottir, Rosa B Barrowdale, Daniel Barwell, Julian Freeman, Laura E. Beane Beauparlant, Charles Joly Beckmann, Matthias W Behrens, Sabine Benitez, Javier Berger, Raanan Bermisheva, Marina Blanco, Amie M Blomqvist, Carl Bogdanova, Natalia Bojesen, Anders Bojesen, Stig E Bonanni, Bernardo Borg, Ake Brady, Angela F Brauch, Hiltrud Brenner, Hermann Bruening, Thomas Burwinkel, Barbara Buys, Saundra S Caldes, Trinidad Caliebe, Almuth Caligo, Maria A Campa, Daniele Campbell, Ian G Canzian, Federico Castelao, Jose E Chang-Claude, Jenny Chanock, Stephen J Claes, Kathleen B.M Clarke, Christine L Collavoli, Anita Conner, Thomas A Cox, David G Cybulski, Cezary Czene, Kamila Daly, Mary B de la Hoya, Miguel Devilee, Peter Diez, Orland Ding, Yuan Chun Dite, Gillian S Ditsch, Nina Domchek, Susan M Dorfling, Cecilia M dos-Santos-Silva, Isabel Durda, Katarzyna Dwek, Miriam Eccles, Diana M Ekici, Arif B Eliassen, A. Heather Ellberg, Carolina Eriksson, Mikael Evans, D. Gareth Fasching, Peter A Figueroa, Jonine Flyger, Henrik Foulkes, William D Friebel, Tara M Friedman, Eitan Gabrielson, Marike Gaddam, Pragna Gago-Dominguez, Manuela |
| description | Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors. |
| format | Article |
| fullrecord | <record><control><sourceid>kuleuven</sourceid><recordid>TN_cdi_kuleuven_dspace_123456789_653054</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>123456789_653054</sourcerecordid><originalsourceid>FETCH-kuleuven_dspace_123456789_6530543</originalsourceid><addsrcrecordid>eNqVy7tuwkAQheFVBFIQ8A7TpUBGNnuxSYdQEA1U1FjDMpgFa7F21iaPD0WKlFCdv_jOhxjMZK4SZfK8968_xZj5kqZppkwx19lA7HdngtViu9x8N9NFqIwuIIbWW4zOV9BhcOgjOAZkvlmHkY5wd_EMwfEVbqendk1NiafqeekIDoGQI1j0lsJI9E9YM43_dii-Vj-75Tq5tjW1HfnyyA1aKrOZVNrkxbw0WqZayXfk5DVZxt8oHw3cU6M</addsrcrecordid><sourcetype>Institutional Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer</title><source>Lirias (KU Leuven Association)</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><creator>Figlioli, Gisella ; Bogliolo, Massimo ; Catucci, Irene ; Caleca, Laura ; Viz Lasheras, Sandra ; Pujol, Roser ; Kiiski, Johanna ; Muranen, Taru A ; Barnes, Daniel R ; Dennis, Joe ; Michailidou, Kyriaki ; Bolla, Manjeet K ; Leslie, Goska ; Aalfs, Cora M ; Adank, Muriel A ; Adlard, Julian ; Agata, Simona ; Cadoo, Karen ; Agnarsson, Bjarni A ; Ahearn, Thomas ; Aittomaki, Kristiina ; Ambrosone, Christine B ; Andrews, Lesley ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arndt, Volker ; Arnold, Norbert ; Aronson, Kristan J ; Arun, Banu K ; Asseryanis, Ella ; Auber, Bernd ; Auvinen, Paivi ; Azzollini, Jacopo ; Balmana, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Barwell, Julian ; Freeman, Laura E. Beane ; Beauparlant, Charles Joly ; Beckmann, Matthias W ; Behrens, Sabine ; Benitez, Javier ; Berger, Raanan ; Bermisheva, Marina ; Blanco, Amie M ; Blomqvist, Carl ; Bogdanova, Natalia ; Bojesen, Anders ; Bojesen, Stig E ; Bonanni, Bernardo ; Borg, Ake ; Brady, Angela F ; Brauch, Hiltrud ; Brenner, Hermann ; Bruening, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Caldes, Trinidad ; Caliebe, Almuth ; Caligo, Maria A ; Campa, Daniele ; Campbell, Ian G ; Canzian, Federico ; Castelao, Jose E ; Chang-Claude, Jenny ; Chanock, Stephen J ; Claes, Kathleen B.M ; Clarke, Christine L ; Collavoli, Anita ; Conner, Thomas A ; Cox, David G ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Ditsch, Nina ; Domchek, Susan M ; Dorfling, Cecilia M ; dos-Santos-Silva, Isabel ; Durda, Katarzyna ; Dwek, Miriam ; Eccles, Diana M ; Ekici, Arif B ; Eliassen, A. Heather ; Ellberg, Carolina ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A ; Figueroa, Jonine ; Flyger, Henrik ; Foulkes, William D ; Friebel, Tara M ; Friedman, Eitan ; Gabrielson, Marike ; Gaddam, Pragna ; Gago-Dominguez, Manuela</creator><creatorcontrib>Figlioli, Gisella ; Bogliolo, Massimo ; Catucci, Irene ; Caleca, Laura ; Viz Lasheras, Sandra ; Pujol, Roser ; Kiiski, Johanna ; Muranen, Taru A ; Barnes, Daniel R ; Dennis, Joe ; Michailidou, Kyriaki ; Bolla, Manjeet K ; Leslie, Goska ; Aalfs, Cora M ; Adank, Muriel A ; Adlard, Julian ; Agata, Simona ; Cadoo, Karen ; Agnarsson, Bjarni A ; Ahearn, Thomas ; Aittomaki, Kristiina ; Ambrosone, Christine B ; Andrews, Lesley ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arndt, Volker ; Arnold, Norbert ; Aronson, Kristan J ; Arun, Banu K ; Asseryanis, Ella ; Auber, Bernd ; Auvinen, Paivi ; Azzollini, Jacopo ; Balmana, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Barwell, Julian ; Freeman, Laura E. Beane ; Beauparlant, Charles Joly ; Beckmann, Matthias W ; Behrens, Sabine ; Benitez, Javier ; Berger, Raanan ; Bermisheva, Marina ; Blanco, Amie M ; Blomqvist, Carl ; Bogdanova, Natalia ; Bojesen, Anders ; Bojesen, Stig E ; Bonanni, Bernardo ; Borg, Ake ; Brady, Angela F ; Brauch, Hiltrud ; Brenner, Hermann ; Bruening, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Caldes, Trinidad ; Caliebe, Almuth ; Caligo, Maria A ; Campa, Daniele ; Campbell, Ian G ; Canzian, Federico ; Castelao, Jose E ; Chang-Claude, Jenny ; Chanock, Stephen J ; Claes, Kathleen B.M ; Clarke, Christine L ; Collavoli, Anita ; Conner, Thomas A ; Cox, David G ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Ditsch, Nina ; Domchek, Susan M ; Dorfling, Cecilia M ; dos-Santos-Silva, Isabel ; Durda, Katarzyna ; Dwek, Miriam ; Eccles, Diana M ; Ekici, Arif B ; Eliassen, A. Heather ; Ellberg, Carolina ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A ; Figueroa, Jonine ; Flyger, Henrik ; Foulkes, William D ; Friebel, Tara M ; Friedman, Eitan ; Gabrielson, Marike ; Gaddam, Pragna ; Gago-Dominguez, Manuela</creatorcontrib><description>Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.</description><identifier>ISSN: 2374-4677</identifier><identifier>EISSN: 2374-4677</identifier><language>eng</language><publisher>NATURE PUBLISHING GROUP</publisher><ispartof>NPJ BREAST CANCER, 2019-11, Vol.5</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,315,776,780,27837</link.rule.ids></links><search><creatorcontrib>Figlioli, Gisella</creatorcontrib><creatorcontrib>Bogliolo, Massimo</creatorcontrib><creatorcontrib>Catucci, Irene</creatorcontrib><creatorcontrib>Caleca, Laura</creatorcontrib><creatorcontrib>Viz Lasheras, Sandra</creatorcontrib><creatorcontrib>Pujol, Roser</creatorcontrib><creatorcontrib>Kiiski, Johanna</creatorcontrib><creatorcontrib>Muranen, Taru A</creatorcontrib><creatorcontrib>Barnes, Daniel R</creatorcontrib><creatorcontrib>Dennis, Joe</creatorcontrib><creatorcontrib>Michailidou, Kyriaki</creatorcontrib><creatorcontrib>Bolla, Manjeet K</creatorcontrib><creatorcontrib>Leslie, Goska</creatorcontrib><creatorcontrib>Aalfs, Cora M</creatorcontrib><creatorcontrib>Adank, Muriel A</creatorcontrib><creatorcontrib>Adlard, Julian</creatorcontrib><creatorcontrib>Agata, Simona</creatorcontrib><creatorcontrib>Cadoo, Karen</creatorcontrib><creatorcontrib>Agnarsson, Bjarni A</creatorcontrib><creatorcontrib>Ahearn, Thomas</creatorcontrib><creatorcontrib>Aittomaki, Kristiina</creatorcontrib><creatorcontrib>Ambrosone, Christine B</creatorcontrib><creatorcontrib>Andrews, Lesley</creatorcontrib><creatorcontrib>Anton-Culver, Hoda</creatorcontrib><creatorcontrib>Antonenkova, Natalia N</creatorcontrib><creatorcontrib>Arndt, Volker</creatorcontrib><creatorcontrib>Arnold, Norbert</creatorcontrib><creatorcontrib>Aronson, Kristan J</creatorcontrib><creatorcontrib>Arun, Banu K</creatorcontrib><creatorcontrib>Asseryanis, Ella</creatorcontrib><creatorcontrib>Auber, Bernd</creatorcontrib><creatorcontrib>Auvinen, Paivi</creatorcontrib><creatorcontrib>Azzollini, Jacopo</creatorcontrib><creatorcontrib>Balmana, Judith</creatorcontrib><creatorcontrib>Barkardottir, Rosa B</creatorcontrib><creatorcontrib>Barrowdale, Daniel</creatorcontrib><creatorcontrib>Barwell, Julian</creatorcontrib><creatorcontrib>Freeman, Laura E. 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Heather</creatorcontrib><creatorcontrib>Ellberg, Carolina</creatorcontrib><creatorcontrib>Eriksson, Mikael</creatorcontrib><creatorcontrib>Evans, D. Gareth</creatorcontrib><creatorcontrib>Fasching, Peter A</creatorcontrib><creatorcontrib>Figueroa, Jonine</creatorcontrib><creatorcontrib>Flyger, Henrik</creatorcontrib><creatorcontrib>Foulkes, William D</creatorcontrib><creatorcontrib>Friebel, Tara M</creatorcontrib><creatorcontrib>Friedman, Eitan</creatorcontrib><creatorcontrib>Gabrielson, Marike</creatorcontrib><creatorcontrib>Gaddam, Pragna</creatorcontrib><creatorcontrib>Gago-Dominguez, Manuela</creatorcontrib><title>The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer</title><title>NPJ BREAST CANCER</title><description>Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.</description><issn>2374-4677</issn><issn>2374-4677</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>FZOIL</sourceid><recordid>eNqVy7tuwkAQheFVBFIQ8A7TpUBGNnuxSYdQEA1U1FjDMpgFa7F21iaPD0WKlFCdv_jOhxjMZK4SZfK8968_xZj5kqZppkwx19lA7HdngtViu9x8N9NFqIwuIIbWW4zOV9BhcOgjOAZkvlmHkY5wd_EMwfEVbqendk1NiafqeekIDoGQI1j0lsJI9E9YM43_dii-Vj-75Tq5tjW1HfnyyA1aKrOZVNrkxbw0WqZayXfk5DVZxt8oHw3cU6M</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Figlioli, Gisella</creator><creator>Bogliolo, Massimo</creator><creator>Catucci, Irene</creator><creator>Caleca, Laura</creator><creator>Viz Lasheras, Sandra</creator><creator>Pujol, Roser</creator><creator>Kiiski, Johanna</creator><creator>Muranen, Taru A</creator><creator>Barnes, Daniel R</creator><creator>Dennis, Joe</creator><creator>Michailidou, Kyriaki</creator><creator>Bolla, Manjeet K</creator><creator>Leslie, Goska</creator><creator>Aalfs, Cora M</creator><creator>Adank, Muriel A</creator><creator>Adlard, Julian</creator><creator>Agata, Simona</creator><creator>Cadoo, Karen</creator><creator>Agnarsson, Bjarni A</creator><creator>Ahearn, Thomas</creator><creator>Aittomaki, Kristiina</creator><creator>Ambrosone, Christine B</creator><creator>Andrews, Lesley</creator><creator>Anton-Culver, Hoda</creator><creator>Antonenkova, Natalia N</creator><creator>Arndt, Volker</creator><creator>Arnold, Norbert</creator><creator>Aronson, Kristan J</creator><creator>Arun, Banu K</creator><creator>Asseryanis, Ella</creator><creator>Auber, Bernd</creator><creator>Auvinen, Paivi</creator><creator>Azzollini, Jacopo</creator><creator>Balmana, Judith</creator><creator>Barkardottir, Rosa B</creator><creator>Barrowdale, Daniel</creator><creator>Barwell, Julian</creator><creator>Freeman, Laura E. 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Gareth</creator><creator>Fasching, Peter A</creator><creator>Figueroa, Jonine</creator><creator>Flyger, Henrik</creator><creator>Foulkes, William D</creator><creator>Friebel, Tara M</creator><creator>Friedman, Eitan</creator><creator>Gabrielson, Marike</creator><creator>Gaddam, Pragna</creator><creator>Gago-Dominguez, Manuela</creator><general>NATURE PUBLISHING GROUP</general><scope>FZOIL</scope></search><sort><creationdate>20191101</creationdate><title>The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer</title><author>Figlioli, Gisella ; Bogliolo, Massimo ; Catucci, Irene ; Caleca, Laura ; Viz Lasheras, Sandra ; Pujol, Roser ; Kiiski, Johanna ; Muranen, Taru A ; Barnes, Daniel R ; Dennis, Joe ; Michailidou, Kyriaki ; Bolla, Manjeet K ; Leslie, Goska ; Aalfs, Cora M ; Adank, Muriel A ; Adlard, Julian ; Agata, Simona ; Cadoo, Karen ; Agnarsson, Bjarni A ; Ahearn, Thomas ; Aittomaki, Kristiina ; Ambrosone, Christine B ; Andrews, Lesley ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arndt, Volker ; Arnold, Norbert ; Aronson, Kristan J ; Arun, Banu K ; Asseryanis, Ella ; Auber, Bernd ; Auvinen, Paivi ; Azzollini, Jacopo ; Balmana, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Barwell, Julian ; Freeman, Laura E. Beane ; Beauparlant, Charles Joly ; Beckmann, Matthias W ; Behrens, Sabine ; Benitez, Javier ; Berger, Raanan ; Bermisheva, Marina ; Blanco, Amie M ; Blomqvist, Carl ; Bogdanova, Natalia ; Bojesen, Anders ; Bojesen, Stig E ; Bonanni, Bernardo ; Borg, Ake ; Brady, Angela F ; Brauch, Hiltrud ; Brenner, Hermann ; Bruening, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Caldes, Trinidad ; Caliebe, Almuth ; Caligo, Maria A ; Campa, Daniele ; Campbell, Ian G ; Canzian, Federico ; Castelao, Jose E ; Chang-Claude, Jenny ; Chanock, Stephen J ; Claes, Kathleen B.M ; Clarke, Christine L ; Collavoli, Anita ; Conner, Thomas A ; Cox, David G ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Ditsch, Nina ; Domchek, Susan M ; Dorfling, Cecilia M ; dos-Santos-Silva, Isabel ; Durda, Katarzyna ; Dwek, Miriam ; Eccles, Diana M ; Ekici, Arif B ; Eliassen, A. Heather ; Ellberg, Carolina ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A ; Figueroa, Jonine ; Flyger, Henrik ; Foulkes, William D ; Friebel, Tara M ; Friedman, Eitan ; Gabrielson, Marike ; Gaddam, Pragna ; Gago-Dominguez, Manuela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-kuleuven_dspace_123456789_6530543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Figlioli, Gisella</creatorcontrib><creatorcontrib>Bogliolo, Massimo</creatorcontrib><creatorcontrib>Catucci, Irene</creatorcontrib><creatorcontrib>Caleca, Laura</creatorcontrib><creatorcontrib>Viz Lasheras, Sandra</creatorcontrib><creatorcontrib>Pujol, Roser</creatorcontrib><creatorcontrib>Kiiski, Johanna</creatorcontrib><creatorcontrib>Muranen, Taru A</creatorcontrib><creatorcontrib>Barnes, Daniel R</creatorcontrib><creatorcontrib>Dennis, Joe</creatorcontrib><creatorcontrib>Michailidou, Kyriaki</creatorcontrib><creatorcontrib>Bolla, Manjeet K</creatorcontrib><creatorcontrib>Leslie, Goska</creatorcontrib><creatorcontrib>Aalfs, Cora M</creatorcontrib><creatorcontrib>Adank, Muriel A</creatorcontrib><creatorcontrib>Adlard, Julian</creatorcontrib><creatorcontrib>Agata, Simona</creatorcontrib><creatorcontrib>Cadoo, Karen</creatorcontrib><creatorcontrib>Agnarsson, Bjarni A</creatorcontrib><creatorcontrib>Ahearn, Thomas</creatorcontrib><creatorcontrib>Aittomaki, Kristiina</creatorcontrib><creatorcontrib>Ambrosone, Christine B</creatorcontrib><creatorcontrib>Andrews, Lesley</creatorcontrib><creatorcontrib>Anton-Culver, Hoda</creatorcontrib><creatorcontrib>Antonenkova, Natalia N</creatorcontrib><creatorcontrib>Arndt, Volker</creatorcontrib><creatorcontrib>Arnold, Norbert</creatorcontrib><creatorcontrib>Aronson, Kristan J</creatorcontrib><creatorcontrib>Arun, Banu K</creatorcontrib><creatorcontrib>Asseryanis, Ella</creatorcontrib><creatorcontrib>Auber, Bernd</creatorcontrib><creatorcontrib>Auvinen, Paivi</creatorcontrib><creatorcontrib>Azzollini, Jacopo</creatorcontrib><creatorcontrib>Balmana, Judith</creatorcontrib><creatorcontrib>Barkardottir, Rosa B</creatorcontrib><creatorcontrib>Barrowdale, Daniel</creatorcontrib><creatorcontrib>Barwell, Julian</creatorcontrib><creatorcontrib>Freeman, Laura E. Beane</creatorcontrib><creatorcontrib>Beauparlant, Charles Joly</creatorcontrib><creatorcontrib>Beckmann, Matthias W</creatorcontrib><creatorcontrib>Behrens, Sabine</creatorcontrib><creatorcontrib>Benitez, Javier</creatorcontrib><creatorcontrib>Berger, Raanan</creatorcontrib><creatorcontrib>Bermisheva, Marina</creatorcontrib><creatorcontrib>Blanco, Amie M</creatorcontrib><creatorcontrib>Blomqvist, Carl</creatorcontrib><creatorcontrib>Bogdanova, Natalia</creatorcontrib><creatorcontrib>Bojesen, Anders</creatorcontrib><creatorcontrib>Bojesen, Stig E</creatorcontrib><creatorcontrib>Bonanni, Bernardo</creatorcontrib><creatorcontrib>Borg, Ake</creatorcontrib><creatorcontrib>Brady, Angela F</creatorcontrib><creatorcontrib>Brauch, Hiltrud</creatorcontrib><creatorcontrib>Brenner, Hermann</creatorcontrib><creatorcontrib>Bruening, Thomas</creatorcontrib><creatorcontrib>Burwinkel, Barbara</creatorcontrib><creatorcontrib>Buys, Saundra S</creatorcontrib><creatorcontrib>Caldes, Trinidad</creatorcontrib><creatorcontrib>Caliebe, Almuth</creatorcontrib><creatorcontrib>Caligo, Maria A</creatorcontrib><creatorcontrib>Campa, Daniele</creatorcontrib><creatorcontrib>Campbell, Ian G</creatorcontrib><creatorcontrib>Canzian, Federico</creatorcontrib><creatorcontrib>Castelao, Jose E</creatorcontrib><creatorcontrib>Chang-Claude, Jenny</creatorcontrib><creatorcontrib>Chanock, Stephen J</creatorcontrib><creatorcontrib>Claes, Kathleen B.M</creatorcontrib><creatorcontrib>Clarke, Christine L</creatorcontrib><creatorcontrib>Collavoli, Anita</creatorcontrib><creatorcontrib>Conner, Thomas A</creatorcontrib><creatorcontrib>Cox, David G</creatorcontrib><creatorcontrib>Cybulski, Cezary</creatorcontrib><creatorcontrib>Czene, Kamila</creatorcontrib><creatorcontrib>Daly, Mary B</creatorcontrib><creatorcontrib>de la Hoya, Miguel</creatorcontrib><creatorcontrib>Devilee, Peter</creatorcontrib><creatorcontrib>Diez, Orland</creatorcontrib><creatorcontrib>Ding, Yuan Chun</creatorcontrib><creatorcontrib>Dite, Gillian S</creatorcontrib><creatorcontrib>Ditsch, Nina</creatorcontrib><creatorcontrib>Domchek, Susan M</creatorcontrib><creatorcontrib>Dorfling, Cecilia M</creatorcontrib><creatorcontrib>dos-Santos-Silva, Isabel</creatorcontrib><creatorcontrib>Durda, Katarzyna</creatorcontrib><creatorcontrib>Dwek, Miriam</creatorcontrib><creatorcontrib>Eccles, Diana M</creatorcontrib><creatorcontrib>Ekici, Arif B</creatorcontrib><creatorcontrib>Eliassen, A. Heather</creatorcontrib><creatorcontrib>Ellberg, Carolina</creatorcontrib><creatorcontrib>Eriksson, Mikael</creatorcontrib><creatorcontrib>Evans, D. Gareth</creatorcontrib><creatorcontrib>Fasching, Peter A</creatorcontrib><creatorcontrib>Figueroa, Jonine</creatorcontrib><creatorcontrib>Flyger, Henrik</creatorcontrib><creatorcontrib>Foulkes, William D</creatorcontrib><creatorcontrib>Friebel, Tara M</creatorcontrib><creatorcontrib>Friedman, Eitan</creatorcontrib><creatorcontrib>Gabrielson, Marike</creatorcontrib><creatorcontrib>Gaddam, Pragna</creatorcontrib><creatorcontrib>Gago-Dominguez, Manuela</creatorcontrib><collection>Lirias (KU Leuven Association)</collection><jtitle>NPJ BREAST CANCER</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Figlioli, Gisella</au><au>Bogliolo, Massimo</au><au>Catucci, Irene</au><au>Caleca, Laura</au><au>Viz Lasheras, Sandra</au><au>Pujol, Roser</au><au>Kiiski, Johanna</au><au>Muranen, Taru A</au><au>Barnes, Daniel R</au><au>Dennis, Joe</au><au>Michailidou, Kyriaki</au><au>Bolla, Manjeet K</au><au>Leslie, Goska</au><au>Aalfs, Cora M</au><au>Adank, Muriel A</au><au>Adlard, Julian</au><au>Agata, Simona</au><au>Cadoo, Karen</au><au>Agnarsson, Bjarni A</au><au>Ahearn, Thomas</au><au>Aittomaki, Kristiina</au><au>Ambrosone, Christine B</au><au>Andrews, Lesley</au><au>Anton-Culver, Hoda</au><au>Antonenkova, Natalia N</au><au>Arndt, Volker</au><au>Arnold, Norbert</au><au>Aronson, Kristan J</au><au>Arun, Banu K</au><au>Asseryanis, Ella</au><au>Auber, Bernd</au><au>Auvinen, Paivi</au><au>Azzollini, Jacopo</au><au>Balmana, Judith</au><au>Barkardottir, Rosa B</au><au>Barrowdale, Daniel</au><au>Barwell, Julian</au><au>Freeman, Laura E. Beane</au><au>Beauparlant, Charles Joly</au><au>Beckmann, Matthias W</au><au>Behrens, Sabine</au><au>Benitez, Javier</au><au>Berger, Raanan</au><au>Bermisheva, Marina</au><au>Blanco, Amie M</au><au>Blomqvist, Carl</au><au>Bogdanova, Natalia</au><au>Bojesen, Anders</au><au>Bojesen, Stig E</au><au>Bonanni, Bernardo</au><au>Borg, Ake</au><au>Brady, Angela F</au><au>Brauch, Hiltrud</au><au>Brenner, Hermann</au><au>Bruening, Thomas</au><au>Burwinkel, Barbara</au><au>Buys, Saundra S</au><au>Caldes, Trinidad</au><au>Caliebe, Almuth</au><au>Caligo, Maria A</au><au>Campa, Daniele</au><au>Campbell, Ian G</au><au>Canzian, Federico</au><au>Castelao, Jose E</au><au>Chang-Claude, Jenny</au><au>Chanock, Stephen J</au><au>Claes, Kathleen B.M</au><au>Clarke, Christine L</au><au>Collavoli, Anita</au><au>Conner, Thomas A</au><au>Cox, David G</au><au>Cybulski, Cezary</au><au>Czene, Kamila</au><au>Daly, Mary B</au><au>de la Hoya, Miguel</au><au>Devilee, Peter</au><au>Diez, Orland</au><au>Ding, Yuan Chun</au><au>Dite, Gillian S</au><au>Ditsch, Nina</au><au>Domchek, Susan M</au><au>Dorfling, Cecilia M</au><au>dos-Santos-Silva, Isabel</au><au>Durda, Katarzyna</au><au>Dwek, Miriam</au><au>Eccles, Diana M</au><au>Ekici, Arif B</au><au>Eliassen, A. Heather</au><au>Ellberg, Carolina</au><au>Eriksson, Mikael</au><au>Evans, D. Gareth</au><au>Fasching, Peter A</au><au>Figueroa, Jonine</au><au>Flyger, Henrik</au><au>Foulkes, William D</au><au>Friebel, Tara M</au><au>Friedman, Eitan</au><au>Gabrielson, Marike</au><au>Gaddam, Pragna</au><au>Gago-Dominguez, Manuela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer</atitle><jtitle>NPJ BREAST CANCER</jtitle><date>2019-11-01</date><risdate>2019</risdate><volume>5</volume><issn>2374-4677</issn><eissn>2374-4677</eissn><abstract>Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.</abstract><pub>NATURE PUBLISHING GROUP</pub><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2374-4677 |
| ispartof | NPJ BREAST CANCER, 2019-11, Vol.5 |
| issn | 2374-4677 2374-4677 |
| language | eng |
| recordid | cdi_kuleuven_dspace_123456789_653054 |
| source | Lirias (KU Leuven Association); Nature Free; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access; Springer Nature OA Free Journals |
| title | The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T07%3A14%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-kuleuven&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20FANCM:p.Arg658%20truncating%20variant%20is%20associated%20with%20risk%20of%20triple-negative%20breast%20cancer&rft.jtitle=NPJ%20BREAST%20CANCER&rft.au=Figlioli,%20Gisella&rft.date=2019-11-01&rft.volume=5&rft.issn=2374-4677&rft.eissn=2374-4677&rft_id=info:doi/&rft_dat=%3Ckuleuven%3E123456789_653054%3C/kuleuven%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true |