The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Massimo Bogliolo; Jordi Surrallés i Calonge; Gisella Figlioli; Irene Catucci; Laura Caleca; Sandra Viz Lasheras; Roser Pujol; Johanna I. Kiiski; Taru A. Muranen; Daniel R. Barnes; Joe Dennis; Kyriaki Michailidou; Manjeet K. Bolla; Goska Leslie; Cora M. Aalfs; Muriel A. Adank; Julian Adlard; Simona Agata; Karen Cadoo; Bjarni A. Agnarsson; Thomas Ahearn; Kristiina Aittomäki; Christine B. Ambrosone; Lesley Andrews; Hoda Anton-Culver; Natalia N. Antonenkova; Volker Arndt; Norbert Arnold; Kristan J. Aronson; Banu K. Arun; Ella Asseryanis; Bernd Auber; Päivi Auvinen; Jacopo Azzollini; Judith Balmaña Gelpí; Rosa B. Barkardottir; Daniel Barrowdale; Julian Barwell; Laura E. Beane Freeman; Charles Joly Beauparlant; Matthias W. Beckmann; Sabine Behrens; Javier Benitez; Raanan Berger; Marina Bermisheva; Amie M. Blanco; Carl Blomqvist; Natalia V. Bogdanova; Anders Bojesen; Stig E. Bojesen; Bernardo Bonanni; Åke Borg; Angela F. Brady; Hiltrud Brauch; Hermann Brenner; Thomas Brüning; Barbara Burwinkel; Saundra Buys; Trinidad Caldes; Almuth Caliebe; Maria Caligo; Daniele Campa; Ian Campbell; Federico Canzian; Jose E. Castelao; Jenny Chang-Claude; Stephen J. Chanock; Kathleen Claes; Christine L. Clarke; Anita Collavoli; Thomas A. Conner; David G. Cox; Cezary Cybulski; Kamila Czene; Mary B. Daly; Miguel De la Hoya; Peter Devilee; Orland Diez; Yuan Chun Ding; Gillian S. Dite; Nina Ditsch; Susan M. Domchek; Cecilia M. Dorfling; Isabel dos-Santos-Silva; Katarzyna Durda; Miriam Dwek; Diana M. Eccles; Arif B. Ekici; A. Heather Eliassen; Carolina Ellberg; Mikael Eriksson; D. Gareth Evans; Peter A. Fasching; Jonine Figueroa; Henrik Flyger; William D. Foulkes; Tara M. Friebel; Eitan Friedman; Marike Gabrielson; Pragna Gaddam; Manuela Gago-Dominguez; Chi Gao; Susan M. Gapstur; Judy Garber; Montserrat García-Closas; José A. García-Sáenz; Mia M. Gaudet; Simon A. Gayther; Graham G. Giles; Gord Glendon; Andrew K. Godwin; Mark S. Goldberg; David E. Goldgar; Pascal Guénel; Angelica M. Gutierrez-Barrera; Lothar Haeberle; Christopher A. Haiman; Niclas Håkansson; Per Hall; Ute Hamann; Patricia A. Harrington; Alexander Hein; Jane Heyworth; Peter Hillemanns; Antoinette Hollestelle; John L. Hopper; H. Dean Hosgood; Anthony Howell; Chunling Hu; Peter J. Hulick; David J. Hunter; Evgeny N. Imyanitov; Claudine Isaacs; Milena Jakimovska; Anna Jakubowska; Paul James; Ramunas Janavicius; Wolfgang Janni; Esther M. John; Michael E. Jones; Audrey Jung; Rudolf Kaaks; Beth Y. Karlan; Elza Khusnutdinova; Cari M. Kitahara; Irene Konstantopoulou; Stella Koutros; Peter Kraft; Diether Lambrechts; Conxi Lazaro; Loic Le Marchand; Jenny Lester; Fabienne Lesueur; Jenna Lilyquist; Jennifer T. Loud; Karen H. Lu; Robert N. Luben; Jan Lubinski; Arto Mannermaa; Mehdi Manoochehri; Siranoush Manoukian; Sara Margolin; John W. M. Martens; Tabea Maurer; Dimitrios Mavroudis; Noura Mebirouk; Alfons Meindl; Usha Menon; Austin Miller; Marco Montagna; Katherine L. Nathanson; Susan L. Neuhausen; William G. Newman; Tu Nguyen-Dumont; Finn Cilius Nielsen; Sarah Nielsen; Liene Nikitina-Zake; Kenneth Offit; Edith Olah; Olufunmilayo I. Olopade; Andrew F. Olshan; Janet E. Olson; Håkan Olsson; Ana Osorio; Laura Ottini; Bernard Peissel; Ana Peixoto; Julian Peto; Dijana Plaseska-Karanfilska; Timea Pocza; Nadege Presneau; Miquel Angel Pujana; Kevin Punie; Brigitte Rack; Johanna Rantala; Muhammad U. Rashid; Rohini Rau-Murthy; Gad Rennert; Flavio Lejbkowicz; Valerie Rhenius; Atocha Romero; Matti A. Rookus; Eric A. Ross; Maria Rossing; Vilius Rudaitis; Matthias Ruebner; Emmanouil Saloustros; Kristin Sanden; Marta Santamariña; Maren T. Scheuner; Rita K. Schmutzler; Michael Schneider; Christopher Scott; Leigha Senter; Mitul Shah; Priyanka Sharma; Xiao-Ou Shu; Jacques Simard; Christian F. Singer; Christof Sohn; Penny Soucy; Melissa C. Southey; John J. Spinelli; Linda Steele; Dominique Stoppa-Lyonnet; William J. Tapper; Manuel R. Teixeira; Mary Beth Terry; Mads Thomassen; Jennifer Thompson; Darcy L. Thull; Marc Tischkowitz; Rob A. E. M. Tollenaar; Diana Torres; Melissa A. Troester; Thérèse Truong; Nadine Tung; Michael Untch; Celine M. Vachon; Elizabeth J. van Rensburg; Elke M. van Veen; Ana Vega; Alessandra Viel; Barbara Wappenschmidt; Jeffrey N. Weitzel; Camilla Wendt; Greet Wieme; Alicja Wolk; Xiaohong R. Yang; Wei Zheng; Argyrios Ziogas; Kristin K. Zorn; Alison M. Dunning; Michael Lush; Qin Wang; Lesley McGuffog; Michael T. Parsons; Paul D. P. Pharoah; Florentia Fostira; Amanda E. Toland; Irene L. Andrulis; Susan J. Ramus; Anthony J. Swerdlow; Mark H. Greene; Wendy K. Chung; Roger L. Milne; Georgia Chenevix-Trench; Thilo Dörk; Marjanka K. Schmidt; Douglas F. Easton; Paolo Radice; Eric Hahnen; Antonis C. Antoniou; Fergus J. Couch; Heli Nevanlinna; Paolo Peterlongo

doi:10.1038/s41523-019-0127-5

The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Massimo Bogliolo, Jordi Surrallés i Calonge, Gisella Figlioli, Irene Catucci, Laura Caleca, Sandra Viz Lasheras, Roser Pujol, Johanna I. Kiiski, Taru A. Muranen, Daniel R. Barnes, Joe Dennis, Kyriaki Michailidou, Manjeet K. Bolla, Goska Leslie, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Simona Agata, Karen Cadoo, Bjarni A. AgnarssonThomas Ahearn, Kristiina Aittomäki, Christine B. Ambrosone, Lesley Andrews, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Bernd Auber, Päivi Auvinen, Jacopo Azzollini, Judith Balmaña Gelpí, Rosa B. Barkardottir, Daniel Barrowdale, Julian Barwell, Laura E. Beane Freeman, Charles Joly Beauparlant, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Raanan Berger, Marina Bermisheva, Amie M. Blanco, Carl Blomqvist, Natalia V. Bogdanova, Anders Bojesen, Stig E. Bojesen, Bernardo Bonanni, Åke Borg, Angela F. Brady, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Saundra Buys, Trinidad Caldes, Almuth Caliebe, Maria Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Kathleen Claes, Christine L. Clarke, Anita Collavoli, Thomas A. Conner, David G. Cox, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel De la Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Nina Ditsch, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Katarzyna Durda, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, William D. Foulkes, Tara M. Friebel, Eitan Friedman, Marike Gabrielson, Pragna Gaddam, Manuela Gago-Dominguez, Chi Gao, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Pascal Guénel, Angelica M. Gutierrez-Barrera, Lothar Haeberle, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, John L. Hopper, H. Dean Hosgood, Anthony Howell, Chunling Hu, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Beth Y. Karlan, Elza Khusnutdinova, Cari M. Kitahara, Irene Konstantopoulou, Stella Koutros, Peter Kraft, Diether Lambrechts, Conxi Lazaro, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Jenna Lilyquist, Jennifer T. Loud, Karen H. Lu, Robert N. Luben, Jan Lubinski, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Tabea Maurer, Dimitrios Mavroudis, Noura Mebirouk, Alfons Meindl, Usha Menon, Austin Miller, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, William G. Newman, Tu Nguyen-Dumont, Finn Cilius Nielsen, Sarah Nielsen, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Bernard Peissel, Ana Peixoto, Julian Peto, Dijana Plaseska-Karanfilska, Timea Pocza, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Brigitte Rack, Johanna Rantala, Muhammad U. Rashid, Rohini Rau-Murthy, Gad Rennert, Flavio Lejbkowicz, Valerie Rhenius, Atocha Romero, Matti A. Rookus, Eric A. Ross, Maria Rossing, Vilius Rudaitis, Matthias Ruebner, Emmanouil Saloustros, Kristin Sanden, Marta Santamariña, Maren T. Scheuner, Rita K. Schmutzler, Michael Schneider, Christopher Scott, Leigha Senter, Mitul Shah, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Linda Steele, Dominique Stoppa-Lyonnet, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Mads Thomassen, Jennifer Thompson, Darcy L. Thull, Marc Tischkowitz, Rob A. E. M. Tollenaar, Diana Torres, Melissa A. Troester, Thérèse Truong, Nadine Tung, Michael Untch, Celine M. Vachon, Elizabeth J. van Rensburg, Elke M. van Veen, Ana Vega, Alessandra Viel, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Greet Wieme, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Alison M. Dunning, Michael Lush, Qin Wang, Lesley McGuffog, Michael T. Parsons, Paul D. P. Pharoah, Florentia Fostira, Amanda E. Toland, Irene L. Andrulis, Susan J. Ramus, Anthony J. Swerdlow, Mark H. Greene, Wendy K. Chung, Roger L. Milne, Georgia Chenevix-Trench, Thilo Dörk, Marjanka K. Schmidt, Douglas F. Easton, Paolo Radice, Eric Hahnen, Antonis C. Antoniou, Fergus J. Couch, Heli Nevanlinna, Paolo Peterlongo

Departamento de Genética y Microbiología

Producción científica: Contribución a una revista › Artículo › Investigación › revisión exhaustiva

26 Citas (Scopus)

Resumen

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.

Idioma original	Inglés
Publicación	npj Breast Cancer
Volumen	5
DOI	https://doi.org/10.1038/s41523-019-0127-5
Estado	Publicada - 2019

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10.1038/s41523-019-0127-5

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Bogliolo, M., Surrallés i Calonge, J., Figlioli, G., Catucci, I., Caleca, L., Viz Lasheras, S., Pujol, R., Kiiski, J. I., Muranen, T. A., Barnes, D. R., Dennis, J., Michailidou, K., Bolla, M. K., Leslie, G., Aalfs, C. M., Adank, M. A., Adlard, J., Agata, S., Cadoo, K., ... Peterlongo, P. (2019). The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. npj Breast Cancer, 5. https://doi.org/10.1038/s41523-019-0127-5

@article{f09ce959bc884884a9b414d65bbbe651,

title = "The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer",

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.",

keywords = "Cancer genetics",

author = "Massimo Bogliolo and {Surrall{\'e}s i Calonge}, Jordi and Gisella Figlioli and Irene Catucci and Laura Caleca and {Viz Lasheras}, Sandra and Roser Pujol and Kiiski, {Johanna I.} and Muranen, {Taru A.} and Barnes, {Daniel R.} and Joe Dennis and Kyriaki Michailidou and Bolla, {Manjeet K.} and Goska Leslie and Aalfs, {Cora M.} and Adank, {Muriel A.} and Julian Adlard and Simona Agata and Karen Cadoo and Agnarsson, {Bjarni A.} and Thomas Ahearn and Kristiina Aittom{\"a}ki and Ambrosone, {Christine B.} and Lesley Andrews and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Volker Arndt and Norbert Arnold and Aronson, {Kristan J.} and Arun, {Banu K.} and Ella Asseryanis and Bernd Auber and P{\"a}ivi Auvinen and Jacopo Azzollini and {Balma{\~n}a Gelp{\'i}}, Judith and Barkardottir, {Rosa B.} and Daniel Barrowdale and Julian Barwell and {Beane Freeman}, {Laura E.} and Beauparlant, {Charles Joly} and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Raanan Berger and Marina Bermisheva and Blanco, {Amie M.} and Carl Blomqvist and Bogdanova, {Natalia V.} and Anders Bojesen and Bojesen, {Stig E.} and Bernardo Bonanni and {\AA}ke Borg and Brady, {Angela F.} and Hiltrud Brauch and Hermann Brenner and Thomas Br{\"u}ning and Barbara Burwinkel and Saundra Buys and Trinidad Caldes and Almuth Caliebe and Maria Caligo and Daniele Campa and Ian Campbell and Federico Canzian and Castelao, {Jose E.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Kathleen Claes and Clarke, {Christine L.} and Anita Collavoli and Conner, {Thomas A.} and Cox, {David G.} and Cezary Cybulski and Kamila Czene and Daly, {Mary B.} and {De la Hoya}, Miguel and Peter Devilee and Orland Diez and Ding, {Yuan Chun} and Dite, {Gillian S.} and Nina Ditsch and Domchek, {Susan M.} and Dorfling, {Cecilia M.} and Isabel dos-Santos-Silva and Katarzyna Durda and Miriam Dwek and Eccles, {Diana M.} and Ekici, {Arif B.} and Eliassen, {A. Heather} and Carolina Ellberg and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Jonine Figueroa and Henrik Flyger and Foulkes, {William D.} and Friebel, {Tara M.} and Eitan Friedman and Marike Gabrielson and Pragna Gaddam and Manuela Gago-Dominguez and Chi Gao and Gapstur, {Susan M.} and Judy Garber and Montserrat Garc{\'i}a-Closas and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A.} and Gaudet, {Mia M.} and Gayther, {Simon A.} and Giles, {Graham G.} and Gord Glendon and Godwin, {Andrew K.} and Goldberg, {Mark S.} and Goldgar, {David E.} and Pascal Gu{\'e}nel and Gutierrez-Barrera, {Angelica M.} and Lothar Haeberle and Haiman, {Christopher A.} and Niclas H{\aa}kansson and Per Hall and Ute Hamann and Harrington, {Patricia A.} and Alexander Hein and Jane Heyworth and Peter Hillemanns and Antoinette Hollestelle and Hopper, {John L.} and Hosgood, {H. Dean} and Anthony Howell and Chunling Hu and Hulick, {Peter J.} and Hunter, {David J.} and Imyanitov, {Evgeny N.} and Claudine Isaacs and Milena Jakimovska and Anna Jakubowska and Paul James and Ramunas Janavicius and Wolfgang Janni and John, {Esther M.} and Jones, {Michael E.} and Audrey Jung and Rudolf Kaaks and Karlan, {Beth Y.} and Elza Khusnutdinova and Kitahara, {Cari M.} and Irene Konstantopoulou and Stella Koutros and Peter Kraft and Diether Lambrechts and Conxi Lazaro and {Le Marchand}, Loic and Jenny Lester and Fabienne Lesueur and Jenna Lilyquist and Loud, {Jennifer T.} and Lu, {Karen H.} and Luben, {Robert N.} and Jan Lubinski and Arto Mannermaa and Mehdi Manoochehri and Siranoush Manoukian and Sara Margolin and Martens, {John W. M.} and Tabea Maurer and Dimitrios Mavroudis and Noura Mebirouk and Alfons Meindl and Usha Menon and Austin Miller and Marco Montagna and Nathanson, {Katherine L.} and Neuhausen, {Susan L.} and Newman, {William G.} and Tu Nguyen-Dumont and Nielsen, {Finn Cilius} and Sarah Nielsen and Liene Nikitina-Zake and Kenneth Offit and Edith Olah and Olopade, {Olufunmilayo I.} and Olshan, {Andrew F.} and Olson, {Janet E.} and H{\aa}kan Olsson and Ana Osorio and Laura Ottini and Bernard Peissel and Ana Peixoto and Julian Peto and Dijana Plaseska-Karanfilska and Timea Pocza and Nadege Presneau and Pujana, {Miquel Angel} and Kevin Punie and Brigitte Rack and Johanna Rantala and Rashid, {Muhammad U.} and Rohini Rau-Murthy and Gad Rennert and Flavio Lejbkowicz and Valerie Rhenius and Atocha Romero and Rookus, {Matti A.} and Ross, {Eric A.} and Maria Rossing and Vilius Rudaitis and Matthias Ruebner and Emmanouil Saloustros and Kristin Sanden and Marta Santamari{\~n}a and Scheuner, {Maren T.} and Schmutzler, {Rita K.} and Michael Schneider and Christopher Scott and Leigha Senter and Mitul Shah and Priyanka Sharma and Xiao-Ou Shu and Jacques Simard and Singer, {Christian F.} and Christof Sohn and Penny Soucy and Southey, {Melissa C.} and Spinelli, {John J.} and Linda Steele and Dominique Stoppa-Lyonnet and Tapper, {William J.} and Teixeira, {Manuel R.} and Terry, {Mary Beth} and Mads Thomassen and Jennifer Thompson and Thull, {Darcy L.} and Marc Tischkowitz and Tollenaar, {Rob A. E. M.} and Diana Torres and Troester, {Melissa A.} and Th{\'e}r{\`e}se Truong and Nadine Tung and Michael Untch and Vachon, {Celine M.} and {van Rensburg}, {Elizabeth J.} and {van Veen}, {Elke M.} and Ana Vega and Alessandra Viel and Barbara Wappenschmidt and Weitzel, {Jeffrey N.} and Camilla Wendt and Greet Wieme and Alicja Wolk and Yang, {Xiaohong R.} and Wei Zheng and Argyrios Ziogas and Zorn, {Kristin K.} and Dunning, {Alison M.} and Michael Lush and Qin Wang and Lesley McGuffog and Parsons, {Michael T.} and Pharoah, {Paul D. P.} and Florentia Fostira and Toland, {Amanda E.} and Andrulis, {Irene L.} and Ramus, {Susan J.} and Swerdlow, {Anthony J.} and Greene, {Mark H.} and Chung, {Wendy K.} and Milne, {Roger L.} and Georgia Chenevix-Trench and Thilo D{\"o}rk and Schmidt, {Marjanka K.} and Easton, {Douglas F.} and Paolo Radice and Eric Hahnen and Antoniou, {Antonis C.} and Couch, {Fergus J.} and Heli Nevanlinna and Paolo Peterlongo",

year = "2019",

doi = "10.1038/s41523-019-0127-5",

language = "English",

volume = "5",

journal = "npj Breast Cancer",

issn = "2374-4677",

publisher = "Nature Publishing Group",

}

Bogliolo, M , Surrallés i Calonge, J, Figlioli, G, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, JI, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomäki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmaña Gelpí, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Beane Freeman, LE, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, NV, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, Å, Brady, AF, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Buys, S, Caldes, T, Caliebe, A, Caligo, M, Campa, D, Campbell, I, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, K, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, De la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guénel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Pujana, MA, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamariña, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Dörk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H & Peterlongo, P 2019, 'The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer', npj Breast Cancer, vol. 5. https://doi.org/10.1038/s41523-019-0127-5

TY - JOUR

T1 - The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

AU - Bogliolo, Massimo

AU - Surrallés i Calonge, Jordi

AU - Figlioli, Gisella

AU - Catucci, Irene

AU - Caleca, Laura

AU - Viz Lasheras, Sandra

AU - Pujol, Roser

AU - Kiiski, Johanna I.

AU - Muranen, Taru A.

AU - Barnes, Daniel R.

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Leslie, Goska

AU - Aalfs, Cora M.

AU - Adank, Muriel A.

AU - Adlard, Julian

AU - Agata, Simona

AU - Cadoo, Karen

AU - Agnarsson, Bjarni A.

AU - Ahearn, Thomas

AU - Aittomäki, Kristiina

AU - Ambrosone, Christine B.

AU - Andrews, Lesley

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arndt, Volker

AU - Arnold, Norbert

AU - Aronson, Kristan J.

AU - Arun, Banu K.

AU - Asseryanis, Ella

AU - Auber, Bernd

AU - Auvinen, Päivi

AU - Azzollini, Jacopo

AU - Balmaña Gelpí, Judith

AU - Barkardottir, Rosa B.

AU - Barrowdale, Daniel

AU - Barwell, Julian

AU - Beane Freeman, Laura E.

AU - Beauparlant, Charles Joly

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Berger, Raanan

AU - Bermisheva, Marina

AU - Blanco, Amie M.

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Anders

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Borg, Åke

AU - Brady, Angela F.

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Buys, Saundra

AU - Caldes, Trinidad

AU - Caliebe, Almuth

AU - Caligo, Maria

AU - Campa, Daniele

AU - Campbell, Ian

AU - Canzian, Federico

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Claes, Kathleen

AU - Clarke, Christine L.

AU - Collavoli, Anita

AU - Conner, Thomas A.

AU - Cox, David G.

AU - Cybulski, Cezary

AU - Czene, Kamila

AU - Daly, Mary B.

AU - De la Hoya, Miguel

AU - Devilee, Peter

AU - Diez, Orland

AU - Ding, Yuan Chun

AU - Dite, Gillian S.

AU - Ditsch, Nina

AU - Domchek, Susan M.

AU - Dorfling, Cecilia M.

AU - dos-Santos-Silva, Isabel

AU - Durda, Katarzyna

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ekici, Arif B.

AU - Eliassen, A. Heather

AU - Ellberg, Carolina

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Foulkes, William D.

AU - Friebel, Tara M.

AU - Friedman, Eitan

AU - Gabrielson, Marike

AU - Gaddam, Pragna

AU - Gago-Dominguez, Manuela

AU - Gao, Chi

AU - Gapstur, Susan M.

AU - Garber, Judy

AU - García-Closas, Montserrat

AU - García-Sáenz, José A.

AU - Gaudet, Mia M.

AU - Gayther, Simon A.

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Godwin, Andrew K.

AU - Goldberg, Mark S.

AU - Goldgar, David E.

AU - Guénel, Pascal

AU - Gutierrez-Barrera, Angelica M.

AU - Haeberle, Lothar

AU - Haiman, Christopher A.

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Harrington, Patricia A.

AU - Hein, Alexander

AU - Heyworth, Jane

AU - Hillemanns, Peter

AU - Hollestelle, Antoinette

AU - Hopper, John L.

AU - Hosgood, H. Dean

AU - Howell, Anthony

AU - Hu, Chunling

AU - Hulick, Peter J.

AU - Hunter, David J.

AU - Imyanitov, Evgeny N.

AU - Isaacs, Claudine

AU - Jakimovska, Milena

AU - Jakubowska, Anna

AU - James, Paul

AU - Janavicius, Ramunas

AU - Janni, Wolfgang

AU - John, Esther M.

AU - Jones, Michael E.

AU - Jung, Audrey

AU - Kaaks, Rudolf

AU - Karlan, Beth Y.

AU - Khusnutdinova, Elza

AU - Kitahara, Cari M.

AU - Konstantopoulou, Irene

AU - Koutros, Stella

AU - Kraft, Peter

AU - Lambrechts, Diether

AU - Lazaro, Conxi

AU - Le Marchand, Loic

AU - Lester, Jenny

AU - Lesueur, Fabienne

AU - Lilyquist, Jenna

AU - Loud, Jennifer T.

AU - Lu, Karen H.

AU - Luben, Robert N.

AU - Lubinski, Jan

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Martens, John W. M.

AU - Maurer, Tabea

AU - Mavroudis, Dimitrios

AU - Mebirouk, Noura

AU - Meindl, Alfons

AU - Menon, Usha

AU - Miller, Austin

AU - Montagna, Marco

AU - Nathanson, Katherine L.

AU - Neuhausen, Susan L.

AU - Newman, William G.

AU - Nguyen-Dumont, Tu

AU - Nielsen, Finn Cilius

AU - Nielsen, Sarah

AU - Nikitina-Zake, Liene

AU - Offit, Kenneth

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Olshan, Andrew F.

AU - Olson, Janet E.

AU - Olsson, Håkan

AU - Osorio, Ana

AU - Ottini, Laura

AU - Peissel, Bernard

AU - Peixoto, Ana

AU - Peto, Julian

AU - Plaseska-Karanfilska, Dijana

AU - Pocza, Timea

AU - Presneau, Nadege

AU - Pujana, Miquel Angel

AU - Punie, Kevin

AU - Rack, Brigitte

AU - Rantala, Johanna

AU - Rashid, Muhammad U.

AU - Rau-Murthy, Rohini

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Rhenius, Valerie

AU - Romero, Atocha

AU - Rookus, Matti A.

AU - Ross, Eric A.

AU - Rossing, Maria

AU - Rudaitis, Vilius

AU - Ruebner, Matthias

AU - Saloustros, Emmanouil

AU - Sanden, Kristin

AU - Santamariña, Marta

AU - Scheuner, Maren T.

AU - Schmutzler, Rita K.

AU - Schneider, Michael

AU - Scott, Christopher

AU - Senter, Leigha

AU - Shah, Mitul

AU - Sharma, Priyanka

AU - Shu, Xiao-Ou

AU - Simard, Jacques

AU - Singer, Christian F.

AU - Sohn, Christof

AU - Soucy, Penny

AU - Southey, Melissa C.

AU - Spinelli, John J.

AU - Steele, Linda

AU - Stoppa-Lyonnet, Dominique

AU - Tapper, William J.

AU - Teixeira, Manuel R.

AU - Terry, Mary Beth

AU - Thomassen, Mads

AU - Thompson, Jennifer

AU - Thull, Darcy L.

AU - Tischkowitz, Marc

AU - Tollenaar, Rob A. E. M.

AU - Torres, Diana

AU - Troester, Melissa A.

AU - Truong, Thérèse

AU - Tung, Nadine

AU - Untch, Michael

AU - Vachon, Celine M.

AU - van Rensburg, Elizabeth J.

AU - van Veen, Elke M.

AU - Vega, Ana

AU - Viel, Alessandra

AU - Wappenschmidt, Barbara

AU - Weitzel, Jeffrey N.

AU - Wendt, Camilla

AU - Wieme, Greet

AU - Wolk, Alicja

AU - Yang, Xiaohong R.

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Zorn, Kristin K.

AU - Dunning, Alison M.

AU - Lush, Michael

AU - Wang, Qin

AU - McGuffog, Lesley

AU - Parsons, Michael T.

AU - Pharoah, Paul D. P.

AU - Fostira, Florentia

AU - Toland, Amanda E.

AU - Andrulis, Irene L.

AU - Ramus, Susan J.

AU - Swerdlow, Anthony J.

AU - Greene, Mark H.

AU - Chung, Wendy K.

AU - Milne, Roger L.

AU - Chenevix-Trench, Georgia

AU - Dörk, Thilo

AU - Schmidt, Marjanka K.

AU - Easton, Douglas F.

AU - Radice, Paolo

AU - Hahnen, Eric

AU - Antoniou, Antonis C.

AU - Couch, Fergus J.

AU - Nevanlinna, Heli

AU - Peterlongo, Paolo

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Cancer genetics

U2 - 10.1038/s41523-019-0127-5

DO - 10.1038/s41523-019-0127-5

M3 - Article

C2 - 31700994

SN - 2374-4677

VL - 5

JO - npj Breast Cancer

JF - npj Breast Cancer

ER -

The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

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