Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers /

Christopher Hakkaart; John F Pearson; Louise Marquart; Joe Dennis; George A R Wiggins; Daniel R Barnes; Bridget A Robinson; Peter D Mace; Kristiina Aittomäki; Irene L Andrulis; Banu K Arun; Jacopo Azzollini; Judith Balmaña; Rosa B Barkardottir; Sami Belhadj; Lieke Berger; Marinus J Blok; Susanne E Boonen; Julika Borde; Angela R Bradbury; Joan Brunet; Saundra S Buys; Maria A Caligo; Ian Campbell; Wendy K Chung; Kathleen B M Claes; Marie-Agnès Collonge-Rame; Jackie Cook; Casey Cosgrove; Fergus J Couch; Mary B Daly; Sita Dandiker; Rosemarie Davidson; Miguel de la Hoya; Robin de Putter; Capucine Delnatte; Mallika Dhawan; Orland Diez; Yuan Chun Ding; Susan M Domchek; Alan Donaldson; Jacqueline Eason; Douglas F Easton; Hans Ehrencrona; Christoph Engel; D Gareth Evans; Ulrike Faust; Lidia Feliubadaló; Florentia Fostira; Eitan Friedman; Megan Frone; Debra Frost; Judy Garber; Simon A Gayther; Andrea Gehrig; Paul Gesta; Andrew K Godwin; David E Goldgar; Mark H Greene; Eric Hahnen; Christopher R Hake; Ute Hamann; Thomas V O Hansen; Jan Hauke; Julia Hentschel; Natalie Herold; Ellen Honisch; Peter J Hulick; Evgeny N Imyanitov; Claudine Isaacs; Louise Izatt; Angel Izquierdo; Anna Jakubowska; Paul A James; Ramūnas Janavičius; Esther M John; Vijai Joseph; Beth Y Karlan; Zoe Kemp; Judy Kirk; Irene Konstantopoulou; Marco Koudijs; Ava Kwong; Yael Laitman; Fiona Lalloo; Christine Lasset; Charlotte Lautrup; Conxi Lazaro; Clémentine Legrand; Goska Leslie; Fabienne Lesueur; Phuong L Mai; Siranoush Manoukian; Véronique Mari; John W M Martens; Lesley McGuffog; Noura Mebirouk; Alfons Meindl; Austin Miller; Marco Montagna; Lidia Moserle; Emmanuelle Mouret-Fourme; Hannah Musgrave; Sophie Nambot; Katherine L Nathanson; Susan L Neuhausen; Heli Nevanlinna; Joanne Ngeow Yuen Yie; Tu Nguyen-Dumont; Liene Nikitina-Zake; Kenneth Offit; Edith Olah; Olufunmilayo I Olopade; Ana Osorio; Claus-Eric Ott; Sue K Park; Michael T Parsons; Inge Sokilde Pedersen; Ana Peixoto; Pedro Perez-Segura; Paolo Peterlongo; Timea Pocza; Paolo Radice; Juliane Ramser; Johanna Rantala; Gustavo C Rodriguez; Karina Rønlund; Efraim H Rosenberg; Maria Rossing; Rita K Schmutzler; Payal D Shah; Saba Sharif; Priyanka Sharma; Lucy E Side; Jacques Simard; Christian F Singer; Katie Snape; Doris Steinemann; Dominique Stoppa-Lyonnet; Christian Sutter; Yen Yen Tan; Manuel R Teixeira; Soo Hwang Teo; Mads Thomassen; Darcy L Thull; Marc Tischkowitz; Amanda E Toland; Alison H Trainer; Vishakha Tripathi; Nadine Tung; Klaartje van Engelen; Elizabeth J van Rensburg; Ana Vega; Alessandra Viel; Lisa Walker; Jeffrey N Weitzel; Marike R Wevers; Georgia Chenevix-Trench; Amanda B Spurdle; Antonis C Antoniou; Logan C Walker

doi:10.1038/s42003-022-03978-6

Title	Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers /
Authors	Hakkaart, Christopher ; Pearson, John F ; Marquart, Louise ; Dennis, Joe ; Wiggins, George A R ; Barnes, Daniel R ; Robinson, Bridget A ; Mace, Peter D ; Aittomäki, Kristiina ; Andrulis, Irene L ; Arun, Banu K ; Azzollini, Jacopo ; Balmaña, Judith ; Barkardottir, Rosa B ; Belhadj, Sami ; Berger, Lieke ; Blok, Marinus J ; Boonen, Susanne E ; Borde, Julika ; Bradbury, Angela R ; Brunet, Joan ; Buys, Saundra S ; Caligo, Maria A ; Campbell, Ian ; Chung, Wendy K ; Claes, Kathleen B M ; Collonge-Rame, Marie-Agnès ; Cook, Jackie ; Cosgrove, Casey ; Couch, Fergus J ; Daly, Mary B ; Dandiker, Sita ; Davidson, Rosemarie ; de la Hoya, Miguel ; de Putter, Robin ; Delnatte, Capucine ; Dhawan, Mallika ; Diez, Orland ; Ding, Yuan Chun ; Domchek, Susan M ; Donaldson, Alan ; Eason, Jacqueline ; Easton, Douglas F ; Ehrencrona, Hans ; Engel, Christoph ; Evans, D Gareth ; Faust, Ulrike ; Feliubadaló, Lidia ; Fostira, Florentia ; Friedman, Eitan ; Frone, Megan ; Frost, Debra ; Garber, Judy ; Gayther, Simon A ; Gehrig, Andrea ; Gesta, Paul ; Godwin, Andrew K ; Goldgar, David E ; Greene, Mark H ; Hahnen, Eric ; Hake, Christopher R ; Hamann, Ute ; Hansen, Thomas V O ; Hauke, Jan ; Hentschel, Julia ; Herold, Natalie ; Honisch, Ellen ; Hulick, Peter J ; Imyanitov, Evgeny N ; Isaacs, Claudine ; Izatt, Louise ; Izquierdo, Angel ; Jakubowska, Anna ; James, Paul A ; Janavičius, Ramūnas ; John, Esther M ; Joseph, Vijai ; Karlan, Beth Y ; Kemp, Zoe ; Kirk, Judy ; Konstantopoulou, Irene ; Koudijs, Marco ; Kwong, Ava ; Laitman, Yael ; Lalloo, Fiona ; Lasset, Christine ; Lautrup, Charlotte ; Lazaro, Conxi ; Legrand, Clémentine ; Leslie, Goska ; Lesueur, Fabienne ; Mai, Phuong L ; Manoukian, Siranoush ; Mari, Véronique ; Martens, John W M ; McGuffog, Lesley ; Mebirouk, Noura ; Meindl, Alfons ; Miller, Austin ; Montagna, Marco ; Moserle, Lidia ; Mouret-Fourme, Emmanuelle ; Musgrave, Hannah ; Nambot, Sophie ; Nathanson, Katherine L ; Neuhausen, Susan L ; Nevanlinna, Heli ; Yie, Joanne Ngeow Yuen ; Nguyen-Dumont, Tu ; Nikitina-Zake, Liene ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo I ; Osorio, Ana ; Ott, Claus-Eric ; Park, Sue K ; Parsons, Michael T ; Pedersen, Inge Sokilde ; Peixoto, Ana ; Perez-Segura, Pedro ; Peterlongo, Paolo ; Pocza, Timea ; Radice, Paolo ; Ramser, Juliane ; Rantala, Johanna ; Rodriguez, Gustavo C ; Rønlund, Karina ; Rosenberg, Efraim H ; Rossing, Maria ; Schmutzler, Rita K ; Shah, Payal D ; Sharif, Saba ; Sharma, Priyanka ; Side, Lucy E ; Simard, Jacques ; Singer, Christian F ; Snape, Katie ; Steinemann, Doris ; Stoppa-Lyonnet, Dominique ; Sutter, Christian ; Tan, Yen Yen ; Teixeira, Manuel R ; Teo, Soo Hwang ; Thomassen, Mads ; Thull, Darcy L ; Tischkowitz, Marc ; Toland, Amanda E ; Trainer, Alison H ; Tripathi, Vishakha ; Tung, Nadine ; van Engelen, Klaartje ; van Rensburg, Elizabeth J ; Vega, Ana ; Viel, Alessandra ; Walker, Lisa ; Weitzel, Jeffrey N ; Wevers, Marike R ; Chenevix-Trench, Georgia ; Spurdle, Amanda B ; Antoniou, Antonis C ; Walker, Logan C
DOI	10.1038/s42003-022-03978-6
Full Text
Is Part of	Communications biology.. Berlin : Nature Portfolio. 2022, vol. 5, no. 1, art. no. 1061, p. [1-15].. eISSN 2399-3642
Abstract [eng]	The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Published	Berlin : Nature Portfolio
Type	Journal article
Language	English
Publication date	2022
CC license

„Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers /“